Pyrrolo[3,2-D] pyrimidines that are selective antagonists of A2B adenosine receptors

ABSTRACT

The present invention provides compounds of the following formula and pharmaceutical compositions that are selective antagonists of A 2B  adenosine receptors (ARs). 
                         
These compounds and compositions are useful as pharmaceutical agents.

This application claims benefit of U.S. Provisional Application No.60/824,316, filed Sep. 1, 2006, the disclosure of which is incorporatedherein in its entirety.

FIELD OF THE INVENTION

The present invention relates to pyrrolo[3,2-d]pyrimidin-6-yl compoundsand pharmaceutical compositions that are selective antagonists of theA_(2B) adenosine receptor (AR). These compounds are useful aspharmaceutical agents.

BACKGROUND OF THE INVENTION

The alkylxanthine theophylline (below), a weak non-selective adenosine

antagonist (See Linden, J., et al., Cardiovascular Biology of Purines,eds. G. Burnstock, et al., 1998, pp 1-20), is useful therapeutically forthe treatment of asthma. However, its use is associated with unpleasantside effects, such as insomnia and diuresis. In recent years, the use oftheophylline as a bronchodilator, for relief of asthma, has beensupplanted by drugs of other classes, e.g., selective β₂-adrenergicagonists, corticosteroids, and recently leukotriene antagonists. Thesecompounds also have limitations. Thus, the development of atheophylline-like drug with reduced side effects is still desirable.

It has been recognized that theophylline and its closely relatedanalogue caffeine block endogenous adenosine acting as a local modulatorof adenosine receptors in the brain and other organs at therapeuticallyuseful doses. Adenosine activates four subtypes of G protein-coupledadenosine receptors (ARs), A₁/A_(2A)/A_(2B)/A₃. Enprofylline (below) isanother example of a xanthine that has been reported to block A_(2B)adenosine receptors and is used

to treat asthma. However, this compound only weakly blocks A₁, A_(2A),and A₃ adenosine receptors. It has also been shown by LaNoue et al (U.S.Pat. No. 6,060,481) that selective adenosine A_(2B) antagonists areuseful for improving insulin sensitivity in a patient.

It has been reported that therapeutic concentrations of theophylline orenprofylline block human A_(2B) receptors, and it has been proposed thatantagonists selective for this subtype may have potential use asantiasthmatic agents. (See Feoktistov, I., et al., Pharmacol. Rev. 1997,49, 381-402; and Robeva, A. S., et al., Drug Dev. Res. 1996, 39,243-252). Enprofylline has a reported K_(i) value of 7 μM and issomewhat selective in binding to human A_(2B) ARS. (See Robeva, A. S.,et al., Drug Dev. Res. 1996, 39, 243-252 and Linden, J., et al., Mol.Pharmacol. 1999, 56, 705-713). A_(2B) ARS are expressed in some mastcells, such as the BR line of canine mastocytoma cells, which appear tobe responsible for triggering acute Ca²⁺ mobilization and degranulation.(See Auchampach, J. A., et al., Mol. Pharmacol. 1997, 52, 846-860 andForsyth, P., et al., Inflamm. Res. 1999, 48, 301-307). A_(2B) ARS alsotrigger Ca²⁺ mobilization, and participate in a delayed IL8 release fromhuman HMC-1 mast cells. Other functions associated with the A_(2B) ARare the control of cell growth and gene expression, (See Neary, J., etal., Trends Neurosci. 1996, 19, 13-18) endothelial-dependentvasodilation (See Martin, P. L., et al., J. Pharmacol. Exp. Ther. 1993,265, 248-253), and fluid secretion from intestinal epithelia. (SeeStrohmeier, G. R., et al., J. Biol. Chem. 1995, 270, 2387-2394).Adenosine acting through A_(2B) ARS has also been reported to stimulatechloride permeability in cells expressing the cystic fibrosis transportregulator. (See Clancy, J. P., et al., Am. J. Physiol. 1999, 276,C361-C369.)

Recently Linden et al., (U.S. Pat. No. 6,545,002) have described a newgroup of compounds and pharmaceutical compositions that are selectiveantagonists of A_(2B) adenosine receptors (ARs).

Although adenosine receptor subtype-selective probes are available forthe A₁, A_(2A), and A₃ ARs, only few selective antagonists are known forthe A_(2B) receptor. Therefore, a continuing need exists for compoundsthat are selective A_(2B) receptor antagonists.

SUMMARY OF THE INVENTION

The present invention provides compounds that act as antagonists ofA_(2B) adenosine receptors and stereoisomers and pharmaceuticallyacceptable salts thereof.

The invention also provides pharmaceutical compositions comprising acompound of the present invention or stereoisomer or a pharmaceuticallyacceptable salt thereof in combination with a pharmaceuticallyacceptable excipient.

Additionally, the invention provides a therapeutic method for treating apathological condition or symptom in a mammal, such as a human, whereinthe activity, e.g., over-activity, of adenosine A_(2B) receptors isimplicated in one or more symptoms of the pathology and antagonism(i.e., blocking) is desired to ameliorate such symptoms. Thus, thepresent invention provides a method of treating a disease comprisingadministering a therapeutically effective amount of at least onecompound of the present invention or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein the disease is selected from asthma,allergies, allergic diseases (e.g., allergic rhinitis and sinusitis),autoimmune diseases (e.g., lupus), pulmonary fibrosis, diarrhealdiseases, insulin resistance, diabetes, obesity, prevention of mast celldegranulation associated with ischemia/reperfusion injuries, heartattack, inhibition of angiogenesis in neoplastic tissues, and inhibitionof angiogenesis in diabetic retinopathy or hyperbaric oxygen-inducedretinopathy.

The invention provides a compound of the present invention for use inmedical therapy.

The invention also provides the use of a compound of the presentinvention for the manufacture of a medicament.

The invention also includes a method comprising contacting a compound ofthe present invention, optionally having a radioactive isotope(radionuclide), such as, for example, tritium, radioactive iodine (e.g.,¹²⁵I for binding assays or ¹²³I for Spectral Imaging) and the like, withtarget A_(2B) adenosine receptor sites comprising said receptors, invivo or in vitro, so as to bind to said receptors. Cell membranescomprising bound A_(2B) adenosine receptor sites can be used to measurethe selectivity of test compounds for adenosine receptor subtypes or canbe used as a tool to identify potential therapeutic agents for thetreatment of diseases or conditions associated with A_(2B)-receptormediation, by contacting said agents with said radioligands andreceptors, and measuring the extent of displacement of the radioligandand/or binding of the agent.

DETAILED DESCRIPTION OF THE INVENTION

Applicants have discovered that compounds of the present invention canbe useful for the treatment of diseases associated with deleteriousA_(2B) receptor activation or activity.

In an embodiment, the present invention provides novel compounds offormula I or a stereoisomer or a pharmaceutically acceptable saltthereof:

wherein:

R is selected from: H, OH, C₁₋₆ alkyl, halo-C₁₋₈ alkyl, C₃₋₆ alkenyl,C₃₋₆ alkynyl, (C₃₋₈ cycloalkyl)C₁₋₈ alkylene, (C₄₋₁₀ heterocycle)C₁₋₈alkylene, (C₆₋₁₀ aryl)C₁₋₈ alkylene, and (C₅₋₁₀ heteroaryl)C₁₋₈alkylene, wherein R optionally is substituted by one R^(c);

R^(c) is independently selected from: F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, OC₁₋₆ alkyl, NO₂, —CN, CF₃, and OCF₃;

R¹ and R² are independently selected from: H, C₁₋₈ alkyl, C₃₋₈ alkenyl,C₃₋₈ alkynyl, C₁₋₈ alkoxy, C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₈alkylene, C₄₋₁₀ heterocycle, (C₄₋₁₀ heterocycle)C₁₋₈ alkylene, C₆₋₁₀aryl, (C₆₋₁₀ aryl)C₁₋₈ alkylene, C₅₋₁₀ heteroaryl, and (C₅₋₁₀heteroaryl)C₁₋₈ alkylene, wherein R¹ and R² are independently optionallysubstituted with 1-2 R^(1a);

R^(1a) is independently selected from: F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, —(CH₂)_(a)OR^(a), —(CH₂)_(a)NR^(a)R^(a),—(CH₂)_(a)NHOH, —(CH₂)_(a)NR^(a)NR^(a)R^(a), —(CH₂)_(a)NO₂,—(CH₂)_(a)CN, —(CH₂)_(a)CO₂R^(a), —(CH₂)_(a)C(O)R^(a),—(CH₂)_(a)OC(O)R^(a), —(CH₂)_(a)CONR^(a)R^(a), CF₃, and OCF₃;

R^(a) is independently selected from: H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₈ alkylene, C₄₋₁₀heterocycle, (C₄₋₁₀ heterocycle)C₁₋₈ alkylene, C₆₋₁₀ aryl, (C₆₋₁₀aryl)C₁₋₈ alkylene, C₅₋₁₀ heteroaryl, and (C₅₋₁₀ heteroaryl)C₁₋₈alkylene, wherein the alkyl is optionally interrupted with 1-2heteroatoms selected from the group consisting of —O—, —S(O)_(p)— and—NR^(b)—;

R^(b) is independently selected from the group consisting of H, C₁₋₆alkyl, and benzyl;

R³ is selected from: OH, C₁₋₈ alkoxy, NR^(3a)R^(3b), C₃₋₈ cycloalkyl,C₄₋₁₀ heterocycle, C₆₋₁₀ aryl, and C₅₋₁₀ heteroaryl, wherein thecycloalkyl, heterocycle, aryl, and heteroaryl optionally are substitutedwith 1-2 R^(3c);

R^(3a) and R^(3b) are independently selected from: C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, phenyl, and benzyl;

R^(3c) is independently selected from: F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, —(CH₂)_(a)OR^(a), —(CH₂)_(a)NR^(a)R^(a),—(CH₂)_(a)NHOH, —(CH₂)_(a)NR^(a)NR^(a)R^(a), —(CH₂)_(a)NO₂,—(CH₂)_(a)CN, —(CH₂)_(a)CO₂R^(a), —(CH₂)_(a)C(O)R^(a),—(CH₂)_(a)OC(O)R^(a), —(CH₂)_(a)CONR^(a)R^(a), CF₃, and OCF₃;

X is selected from: (CH₂)_(q), (CH₂)_(r)C(O), and (CH₂)_(r)C(O)NR⁴;

R⁴ is selected from: H, C₁₋₄ alkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl;

Y is selected from: 5-10 membered heteroaryl and 6-10 membered aryl,

wherein Y is optionally substituted with 1-4 Y¹;

Y¹ is independently selected from: F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, —(CH₂)_(a)OR^(a), —(CH₂)_(a)NR^(a)R^(a),—(CH₂)_(a)NHOH, —(CH₂)_(a)NR^(a)NR^(a)R^(a), —(CH₂)_(a)NO₂,—(CH₂)_(a)CN, —(CH₂)_(a)CO₂R^(a), —(CH₂)_(a)C(O)R^(a),—(CH₂)_(a)OC(O)R^(a), —(CH₂)_(a)CONR^(a)R^(a), CF₃, and OCF₃;

a is independently selected from the group consisting of 0, 1, and 2;

n is independently selected from: 1, 2, and 3;

p is independently selected from: 0, 1, and 2;

q is independently selected from 1, 2, 3, and 4; and,

r is independently selected from 0, 1, 2, and 3.

In another embodiment, the present invention provides novel compounds,wherein the compound is of formula II or a stereoisomer or apharmaceutically acceptable salt thereof:

wherein:

R is selected from: H and C₁₋₄ alkyl;

R¹ and R² are independently selected from: H, C₁₋₄ alkyl, C₃₋₄ alkenyl,C₃₋₄ alkynyl, C₃₋₆ cycloalkyl, (C₃₋₆ cycloalkyl)C₁₋₂ alkylene, C₅₋₆heterocycle, (C₅₋₆ heterocycle)C₁₋₂ alkylene, C₆₋₁₀ aryl, (C₆₋₁₀aryl)C₁₋₂ alkylene, C₅₋₁₀ heteroaryl, and (C₅₋₁₀ heteroaryl)C₁₋₂alkylene, wherein R¹ and R² are independently optionally substitutedwith 1-2 R^(1a);

R^(1a) is independently selected from: F, Cl, Br, I, C₁₋₄ alkyl, OR^(a),NR^(a)R^(a), NO₂, —CN, CO₂R^(a), C(O)R^(a), OC(O)R^(a), CONR^(a)R^(a),CF₃, and OCF₃;

R³ is selected from: OCH₃, OCH₂CH₃, NR^(3a)R^(3b), C₃₋₆ cycloalkyl, andC₅₋₆ heterocycle, wherein the cycloalkyl and heterocycle independentlyare optionally substituted with 1-2 R^(3c);

R^(3a) and R^(3b) are independently selected from: C₁₋₄ alkyl, phenyl,and benzyl;

R^(3c) is independently selected from: F, Cl, Br, I, C₁₋₄ alkyl, OR^(a),NR^(a)R^(a), NO₂, —CN, CO₂R^(a), C(O)R^(a), OC(O)R^(a), CONR^(a)R^(a),CF₃, and OCF₃;

Y is selected from: 5-6 membered heteroaryl and phenyl, wherein Y isoptionally substituted with 1-2 Y¹;

Y¹ is independently selected from: F, Cl, Br, I, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, OR^(a), NR^(a)R^(a), NO₂, —CN, CO₂R^(a),C(O)R^(a), OC(O)R^(a), CONR^(a)R^(a), CF₃, and OCF₃; and,

R^(a) is independently selected from: H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,phenyl, and benzyl.

In another embodiment, the present invention provides novel compounds,wherein:

R is H;

R¹ and R² are independently selected from: n-propyl, cyclopropylmethyl,and cyclobutyl;

R³ is selected from: cyclopropyl, cyclobutyl, N-pyrrolidino,N-piperidino, N-piperazino, and N-morpholino;

Y is selected from: pyridyl and pyrimidyl, wherein Y optionally issubstituted with 1-2 Y¹; and,

Y¹ is independently selected from: F, Cl, CH₃, OCH₃, NO₂, —CN, and CF₃.

In another embodiment, the present invention provides novel compounds,wherein:

R¹ is selected from: n-propyl and cyclopropylmethyl; and,

R² is n-propyl.

In another embodiment, the present invention provides novel compounds,wherein:

R¹ is n-propyl; and,

R² is n-propyl.

In another embodiment, the present invention provides novel compounds,wherein the compound is of formula IV or a stereoisomer or apharmaceutically acceptable salt thereof:

wherein:

R is selected from: H and C₁₋₄ alkyl;

R¹ and R² are independently selected from: H, C₁₋₄ alkyl, C₃₋₄ alkenyl,C₃₋₄ alkynyl, C₃₋₆ cycloalkyl, (C₃₋₆ cycloalkyl)C₁₋₂ alkylene, C₅₋₆heterocycle, (C₅₋₆ heterocycle)C₁₋₂ alkylene, C₆₋₁₀ aryl, (C₆₋₁₀aryl)C₁₋₂ alkylene, C₅₋₁₀ heteroaryl, and (C₅₋₁₀ heteroaryl)C₁₋₂alkylene, wherein R¹ and R² are independently optionally substitutedwith 1-2 R^(1a);

R^(1a) is independently selected from: F, Cl, Br, I, C₁₋₄ alkyl, OR^(a),NR^(a)R^(a), NO₂, —CN, CO₂R^(a), C(O)R^(a), OC(O)R^(a), CONR^(a)R^(a),CF₃, and OCF₃;

R³ is selected from: OCH₃, OCH₂CH₃, NR^(3a)R^(3b), C₃₋₆ cycloalkyl, andC₅₋₆ heterocycle, wherein the cycloalkyl and heterocycle independentlyare optionally substituted with 1-2 R^(3c);

R^(3a) and R^(3b) are independently selected from: C₁₋₄ alkyl, phenyl,and benzyl;

R^(3c) is independently selected from: F, Cl, Br, I, C₁₋₄ alkyl, OR^(a),NR^(a)R^(a), NO₂, —CN, CO₂R^(a), C(O)R^(a), OC(O)R^(a), CONR^(a)R^(a),CF₃, and OCF₃;

Y is selected from: 5-6 membered heteroaryl and phenyl, wherein Y isoptionally substituted with 1-2 Y¹;

Y¹ is independently selected from: F, Cl, Br, I, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, OR^(a), NR^(a)R^(a), NO₂, —CN, CO₂R^(a),C(O)R^(a), OC(O)R^(a), CONR^(a)R^(a), CF₃, and OCF₃; and,

R^(a) is independently selected from: H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,phenyl, and benzyl.

In another embodiment, the present invention provides novel compounds,wherein the compound is of formula V or VI or a stereoisomer or apharmaceutically acceptable salt thereof:

In another embodiment, the present invention provides novel compounds,wherein the compound is:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides novel compounds,wherein the compound is selected from Examples 1-396 of Table 1 orExamples 1-396 of Table 2 or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention, there is provided apharmaceutical composition, comprising: (a) a therapeutically effectiveamount of a compound of the present invention; and (b) apharmaceutically acceptable excipient.

In another embodiment of the invention, there is provided a therapeuticmethod for treating a pathological condition or symptom in a mammal,wherein the activity of adenosine A_(2B) receptors is implicated andantagonism of its action is desired, comprising administering to themammal a therapeutically effective amount of a compound of the presentinvention.

In another embodiment of the invention, there is provided a method oftreating a disease comprising administering a therapeutically effectiveamount of at least one compound of the present invention or astereoisomer or pharmaceutically acceptable salt thereof, wherein thedisease is selected from asthma, allergies, allergic diseases (e.g.,allergic rhinitis and sinusitis), autoimmune diseases (e.g., lupus),pulmonary fibrosis, diarrheal diseases, insulin resistance, diabetes,obesity, prevention of mast cell degranulation associated withischemia/reperfusion injuries, heart attack, inhibition of angiogenesisin neoplastic tissues, and inhibition of angiogenesis in diabeticretinopathy or hyperbaric oxygen-induced retinopathy.

In another embodiment of the invention, there is provided the compoundof the present invention for use in medical therapy.

In another embodiment, there is provided a use of a compound of theinvention, for the manufacture of a medicament useful for the treatmentof a disease in a mammal.

Any embodiment or feature of the present invention whether characterizedas preferred or not characterized as preferred may be combined with anyother aspect or feature of the invention, whether such other feature ischaracterized as preferred or not characterized as preferred.

Definitions

The examples provided in this application are non-inclusive unlessotherwise stated. They include but are not limited to the recitedgroups.

The indefinite articles “a” and “an” mean. “at least one” or “one ormore” when used in this application, including the claims, unlessspecifically indicated otherwise.

Examples of the molecular weight of compounds of the present inventioncan include (a) less than about 500, 550, 600, 650, 700, 750, 800, 850,900, 950, or 1000 grams per mole; (b) less than about 950 grams permole; (c) less than about 850 grams per mole, and, (d) less than about750 grams per mole.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

The term “substituted” means that any one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency is not exceeded, andthat the substitution results in a stable compound. When a substituentis keto (i.e., ═O), then 2 hydrogens on the atom are replaced. Ketosubstituents are not present on aromatic moieties.

Stable means that the compound is suitable for pharmaceutical use.

The present invention covers stable compound and thus avoids, unlessotherwise specified, the following bond types: heteroatom-halogen, N—S,O—S, O—O, and S—S.

The present invention includes all isotopes of atoms occurring in thepresent compounds. Isotopes include those atoms having the same atomicnumber but different mass numbers. Isotopes of hydrogen include tritiumand deuterium. Isotopes of carbon include C-13 and C-14.

“Alkyl” includes both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms. C₁₋₆alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups.Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, and s-pentyl.

“Alkenyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more unsaturatedcarbon-carbon bonds that may occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₆ alkenyl includes C₂, C₃, C₄, C₅, andC₆ alkenyl groups.

“Alkynyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more triple carbon-carbonbonds that may occur in any stable point along the chain, such asethynyl and propynyl. C₂₋₆ Alkynyl includes C₂, C₃, C₄, C₅, and C₆alkynyl groups.

“Cycloalkyl” includes the specified number of hydrocarbon atoms in asaturated ring, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. C₃₋₈ cycloalkyl includes C₃,C₄, C₅, C₆, C₇, and C₈ cycloalkyl groups. Cycloalkyl also includebicycloalkyl and tricycloalkyl, both of which include fused and bridgedrings (e.g., norbornane and adamantane).

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

“Aryl” refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 memberedmonocyclic, bicyclic, or tricyclic ring, wherein at least one ring, ifmore than one is present, is aromatic. Examples of aryl includefluorenyl, phenyl, naphthyl, indanyl, and tetrahydronaphthyl.

“Heteroaryl” refers to any stable 5, 6, 7, 8, 9, 10, 11, or 12 membered,(unless the number of members is otherwise recited), monocyclic,bicyclic, or tricyclic heterocyclic ring that is aromatic, and whichconsists of carbon atoms and 1, 2, 3, or 4 heteroatoms independentlyselected from the group consisting of N, O, and S. If the heteroaryl isdefined by the number of carbons atoms, then 1, 2, 3, or 4 of the listedcarbon atoms are replaced by a heteroatom. If the heteroaryl group isbicyclic or tricyclic, then at least one of the two or three rings mustcontain a heteroatom, though both or all three may each contain one ormore heteroatoms. If the heteroaryl group is bicyclic or tricyclic, thenonly one of the rings must be aromatic. The N group may be N, NH, orN-substituent, depending on the chosen ring and if substituents arerecited. The nitrogen and sulfur heteroatoms may optionally be oxidized(e.g., S, S(O), S(O)₂, and N—O). The heteroaryl ring may be attached toits pendant group at any heteroatom or carbon atom that results in astable structure. The heteroaryl rings described herein may besubstituted on carbon or on a nitrogen atom if the resulting compound isstable.

Examples of heteroaryl include acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolyl,1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

“Heterocycle” refers to any stable 4, 5, 6, 7, 8, 9, 10, 11, or 12membered, (unless the number of members is otherwise recited),monocyclic, bicyclic, or tricyclic heterocyclic ring that is saturatedor partially unsaturated, and which consists of carbon atoms and 1, 2,3, or 4 heteroatoms independently selected from the group consisting ofN, O, and S. If the heterocycle is defined by the number of carbonsatoms, then from 1, 2, 3, or 4 of the listed carbon atoms are replacedby a heteroatom. If the heterocycle is bicyclic or tricyclic, then atleast one of the two or three rings must contain a heteroatom, thoughboth or all three may each contain one or more heteroatoms. The N groupmay be N, NH, or N-substituent, depending on the chosen ring and ifsubstituents are recited. The nitrogen and sulfur heteroatoms optionallymay be oxidized (e.g., S, S(O), S(O)₂, and N—O). The heterocycle may beattached to its pendant group at any heteroatom or carbon atom thatresults in a stable structure. The heterocycles described herein may besubstituted on carbon or on a nitrogen atom if the resulting compound isstable.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

Mammal and patient covers warm blooded mammals that are typically undermedical care (e.g., humans and domesticated animals). Examples ofmammals include (a) feline, canine, equine, and bovine and (b) human.

“Treating” or “treatment” covers the treatment of a disease-state in amammal, and includes: (a) preventing the disease-state from occurring ina mammal, in particular, when such mammal is predisposed to thedisease-state but has not yet been diagnosed as having it; (b)inhibiting the disease-state, e.g., arresting its development; and/or(c) relieving the disease-state, e.g., causing regression of the diseasestate until a desired endpoint is reached. Treating also includes theamelioration of a symptom of a disease (e.g., lessen the pain ordiscomfort), wherein such amelioration may or may not be directlyaffecting the disease (e.g., cause, transmission, expression, etc.).

Obesity is defined based upon body mass index (BMI). A subject is obeseif they have a BMI approximately over 30 and is severely obese if theirBMI is approximately over 40.

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic,ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric,edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic,hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic,pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,propionic, salicyclic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,1990, p 1445, the disclosure of which is hereby incorporated byreference.

“Therapeutically effective amount” includes an amount of a compound ofthe present invention that is effective when administered alone or incombination to treat obesity or another indication listed herein.“Therapeutically effective amount” also includes an amount of thecombination of compounds claimed that is effective to treat the desiredindication. The combination of compounds preferably is a synergisticcombination. Synergy, as described, for example, by Chou and Talalay,Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect of thecompounds when administered in combination is greater than the additiveeffect of the compounds when administered alone as a single agent. Ingeneral, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. Synergy can be in terms oflower cytotoxicity, increased effect, or some other beneficial effect ofthe combination compared with the individual components.

The compounds of the present invention may have a chiral center and mayexist in and be isolated in optically active and racemic forms. Somecompounds may exhibit polymorphism. The present invention encompassesany racemic, optically-active, polymorphic, or stereoisomeric form, ormixtures thereof, of a compound of the invention, which possess theuseful properties described herein; it being well known in the art howto prepare optically active forms (for example, by resolution of theracemic form by recrystallization techniques, by synthesis fromoptically-active starting materials, by chiral synthesis, or bychromatographic separation using a chiral stationary phase) and how todetermine therapeutic activity using the standard tests described hereinor using other similar tests which are well known in the art.

Specific and preferred values listed for radicals, substituents, andranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

Dosage and Formulation

The compounds of the present invention can be formulated aspharmaceutical compositions and administered to a mammalian host, suchas a human patient, in a variety of forms adapted to the chosen route ofadministration, e.g., orally or parenterally, by intravenous,intramuscular, topical, inhalation or subcutaneous routes. Exemplarypharmaceutical compositions are disclosed in “Remington: The Science andPractice of Pharmacy”, A. Gennaro, ed., 20th edition, Lippincott,Williams & Wilkins, Philadelphia, Pa.

The present compounds may be systemically administered, e.g., orally, incombination with a pharmaceutically acceptable excipient such as aninert diluent or an assimilable edible carrier. They may be enclosed inhard or soft shell gelatin capsules, may be compressed into tablets ormay be incorporated directly with the food of the patient's diet. Fororal therapeutic administration, the active compound may be combinedwith one or more excipients and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. Such compositions and preparations should contain at least0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 60% of the weight of a given unit dosage form. Theamount of active compound in such therapeutically useful compositions issuch that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills or capsules may be coated withgelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of the present invention to the skin are known tothe art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392),Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157)and Wortzman (U.S. Pat. No. 4,820,508). Useful dosages of the compoundsof the present invention can be determined by comparing their in vitroactivity, and in vivo activity in animal models. Methods for theextrapolation of effective dosages in mice, and other animals, to humansare known to the art; for example, see U.S. Pat. No. 4,938,949.

Generally, the concentration of the compound(s) of the present inventionin a liquid composition, such as a lotion, will be from (a) about 0.1-25wt % and (b) about 0.5-10 wt %. The concentration in a semi-solid orsolid composition such as a gel or a powder will be (a) about 0.1-5 wt %and (b) about 0.5-2.5 wt %.

The amount of the compound or an active salt or derivative thereof,required for use in treatment will vary not only with the particularcompound or salt selected but also with the route of administration, thenature of the condition being treated, and the age and condition of thepatient and will be ultimately at the discretion of the attendantphysician or clinician. In general, however, a suitable dose will be inthe range of from (a) about 1.0-100 mg/kg of body weight per day, (b)about 10-75 mg/kg of body weight per day, and (c) about 5-20 mg perkilogram body weight per day.

The compound can be conveniently administered in unit dosage form; e.g.,tablets, caplets, etc., containing (a) about 4-400 mg, (b) about 10-200mg, and (c) about 20-100 mg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from (a) about 0.02-20μM, (b) about 0.1-10 μM, and (c) about 0.5-5 μM. These concentrationsmay be achieved, for example, by the intravenous injection of a0.005-0.5% solution of the active ingredient, or orally administered asa bolus containing about 4-400 mg of the active ingredient.

The compounds of the invention can also be administered by inhalationfrom an inhaler, insufflator, atomizer or pressurized pack or othermeans of delivering an aerosol spray. Pressurized packs may comprise asuitable propellant such as carbon dioxide or other suitable gas. Incase of a pressurized aerosol, the dosage unit may be determined byproviding a value to deliver a metered amount. The inhalers,insufflators, atomizers are fully described in pharmaceutical referencebooks such as Remington's Pharmaceutical Sciences Volumes 16 (1980) or18 (1990) Mack Publishing Co.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

All patents, patent applications, books and literature cited in thespecification are hereby incorporated by reference in their entirety. Inthe case of any inconsistencies, the present disclosure, including anydefinitions therein will prevail.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention. The present invention,thus generally described, will be understood more readily by referenceto the following examples, which are provided by way of illustration andare not intended to be limiting of the present invention.

EXAMPLES

Pharmacology.

The ability of compounds of the invention to act as an A_(2B) adenosinereceptor antagonists may be determined using pharmacological modelswhich are well known to the art or using test procedures describedbelow.

The rat A_(2B) receptor cDNA was subcloned into the expression plasmidpDoubleTrouble using techniques described in Robeva, A. et al., Biochem.Pharmacol. 1996, 51, 545-555. The plasmid was amplified in competentJM109 cells and plasmid DNA isolated using Wizard Megaprep columns(Promega Corporation, Madison, Wis.). A_(2B) adenosine receptors wereintroduced into HEK-293 cells by means of Lipofectin as described inFelgner, P. L. et al., Proc. Natl. Acad. Sci. USA 1987, 84, 7413-7417.

Cell Culture

Transfected HEK cells were grown under 5% CO₂/95% O₂ humidifiedatmosphere at a temperature of 37° C. Colonies were selected by growthof cells in 0.6 mg/mL G418. Transfected cells were maintained in DMEMsupplemented with Hams F12 nutrient mixture (1/1), 10% newborn calfserum, 2 mM glutamine and containing 50 IU/mL penicillin, 50 mg/mLstreptomycin, and 0.2 mg/mL Geneticin (G418, Boehringer Mannheim). Cellswere cultured in 10 cm diameter round plates and subcultured when grownconfluent (approximately after 72 hours).

Radioligand Binding Studies.

At A_(2B) receptors: Confluent monolayers of HEK-A_(2B) cells werewashed with PBS followed by ice cold Buffer A (10 mM HEPES, 10 mM EDTA,pH 7.4) with protease inhibitors (10 μg/mL benzamidine, 100 μMphenylmethanesulfonyl fluoride, and 2 μg/mL of each aprotinin, pepstatinand leupeptin). The cells were homogenized in a Polytron (Brinkmann) for20 s, centrifuged at 30,000×g, and the pellets washed twice with bufferHE (10 mM HEPES, 1 mM EDTA, pH 7.4 with protease inhibitors). The finalpellet was resuspended in buffer HE, supplemented with 10% sucrose andfrozen in aliquots at −80° C. For binding assays membranes were thawedand diluted 5-10 fold with HE to a final protein concentration ofapproximately 1 mg/mL. To determine protein concentrations, membranes,and bovine serum albumin standards were dissolved in 0.2% NaOH/0.01% SDSand protein determined using fluorescamine fluorescence. Stowell, C. P.et al., Anal. Biochem. 1978, 85, 572-580.

Saturation binding assays for rat A_(2B) adenosine receptors wereperformed with [³H]ZM214,385 (17 Ci/mmol, Tocris Cookson, Bristol UK)(Ji, X. et al., Drug Design Discov. 1999, 16, 216-226) or ¹²⁵I-ABOPX(2200 Ci/mmol). To prepare ¹²⁵I-ABOPX, 10 μL of 1 mM ABOPX in methanol/1M NaOH (20:1) was added to 50 μL of 100 mM phosphate buffer, pH 7.3. Oneor 2 mCi of Na ¹²⁵I was added, followed by 10 μL of 1 mg/mL chloramine-Tin water. After incubation, 20 minutes at room temperature, 50 μL of 10mg/mL Na-metabisulfite in water was added to quench the reaction. Thereaction mixture was applied to a C18 HPLC column, eluting with amixture of methanol and 5 mM phosphate, pH 6.0. After 5 min at 35%methanol, the methanol concentration was ramped to 100% over 15 min.Unreacted ABOPX eluted in 11-12 minutes; ¹²⁵I-ABOPX eluted at 18-19 minin a yield of 50-60% with respect to the initial ¹²⁵I.

In equilibrium binding assays the ratio of ¹²⁷I/¹²⁵I-ABOPX was 10-20/1.Radioligand binding experiments were performed in triplicate with 20-25μg membrane protein in a total volume of 0.1 mL HE buffer supplementedwith 1 U/mL adenosine deaminase and 5 mM MgCl₂. The incubation time was3 h at 21° C. Nonspecific binding was measured in the presence of 100 μMNECA. Competition experiments were carried out using 0.6 nM 125I-ABOPX.Membranes were filtered on Whatman GF/C filters using a Brandel cellharvester (Gaithersburg, Md.) and washed 3 times over 15-20 seconds withice cold buffer (10 mM Tris, 1 mM MgCl₂, pH 7.4). B_(max) and K_(D)values were calculated by Marquardt's nonlinear least squaresinterpolation for single a site binding models. Marquardt, D. M., J.Soc. Indust. Appl. Math. 1963, 11, 431-441.21. K_(i) values fordifferent compounds were derived from IC₅₀ values as described. Linden,J., J. Cycl. Nucl. Res. 1982, 8, 163-172. Data from replicateexperiments are tabulated as means ± SEM.

At other Adenosine Receptors: [³H]CPX. Bruns, R. F. et al.,Naunyn-Schmiedeberg's Arch. Pharmacol. 1987, 335, 59-63. ¹²⁵I-ZM241385and ¹²⁵I-ABA were utilized in radioligand binding assays to membranesderived from HEK-293 cells expressing recombinant rat A₁, A_(2A) and A₃ARS, respectively. Binding of [³H]R—N⁶-phenylisopropyladenosine.Schwabe, U. et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 1980, 313,179-187. ([³H]R-PIA, Amersham, Chicago, Ill.) to A₁ receptors from ratcerebral cortical membranes and of [³H]CGS 21680. Jarvis, M. F. et al.,J. Pharmacol. Exp. Therap. 1989, 251, 888-893. (Dupont NEN, Boston,Mass.) to A_(2A) receptors from rat striatal membranes was performed asdescribed. Adenosine deaminase (3 units/mL) was present during thepreparation of the brain membranes, in a pre-incubation of 30 min at 30°C., and during the incubation with the radioligands. All non-radioactivecompounds were initially dissolved in DMSO, and diluted with buffer tothe final concentration, where the amount of DMSO never exceeded 2%.Incubations were terminated by rapid filtration over Whatman GF/Bfilters, using a Brandell cell harvester (Brandell, Gaithersburg, Md.).The tubes were rinsed three times with 3 mL buffer each.

At least six different concentrations of competitor, spanning 3 ordersof magnitude adjusted appropriately for the IC₅₀ of each compound, wereused. IC₅₀ values, calculated with the nonlinear regression methodimplemented in (Graph-Pad Prism, San Diego, Calif.), were converted toapparent K_(i) values as described. Linden, J., J. Cycl. Nucl. Res.1982, 8, 163-172. Hill coefficients of the tested compounds were in therange of 0.8 to 1.1.

Functional Assay:

HEK-A_(2B) cells from one confluent T75 flask were rinsed with Ca²⁺ andMg²⁺-free Dulbecco's phosphate buffered saline (PBS) and then incubatedin Ca²⁺ and Mg²⁺—free HBSS with 0.05% trypsin and 0.53 mM EDTA until thecells detached. The cells were rinsed twice by centrifugation at 250×gin PBS and resuspended in 10 mL of HBSS composed of 137 mM NaCl, 5 mMKCl, 0.9 mM MgSO₄, 1.4 mM CaCl₂, 3 mM NaHCO₃, 0.6 mM Na₂HPO₄, 0.4 mMKH₃PO₄, 5.6 mM glucose, and 10 mM HEPES, pH 7.4 and the Ca²⁺-sensitivefluorescent dye indo-1-AM (5 μM) 37° C. for 60 min. The cells wererinsed once and resuspended in 25 mL dye-free HBSS supplemented with 1U/ml adenosine deaminase and held at room temperature. Adenosinereceptor antagonists prepared as 100× stocks in DMSO or vehicle wasadded and the cells and transferred to a 37° C. bath for 2 minutes. Thenthe cells (1 million in 2 ml) were transferred to a stirred cuvettemaintained at 37° C. within an Aminco SLM 8000 spectrofluorometer (SMLinstruments, Urbana Ill.). The ratios of indo-1 fluorescence obtained at400 and 485 nm (excitation, 332 nm) was recorded using a slit width of 4nm. NECA was added after a 100 s equilibration period.

Cyclic AMP Accumulation

Cyclic AMP generation was performed in DMEM/HEPES buffer (DMEMcontaining 50 mM HEPES, pH 7.4, 37° C.). Each well of cells was washedtwice with DMEM/HEPES buffer, and then 100 μL adenosine deaminase (finalconcentration 10 IU/mL) and 100 μL of solutions of rolipram andcilostamide (each at a final concentration of 10 μM) were added,followed by 50 μL of the test compound (appropriate concentration) orbuffer. After 15 minutes, incubation at 37° C. was terminated byremoving the medium and adding 200 μL of 0.1 M HCl. Acid extracts werestored at −20° C. until assay. The amounts of cyclic AMP were determinedfollowing a protocol which utilized a cAMP binding protein (PKA) [vander Wenden et al., 1995], with the following minor modifications. Theassay buffer consisted of 150 mM K₂HPO₄/10 mM EDTA/0.2% BSA FV at pH7.5. Samples (20 mL) were incubated for 90 minutes at 0° C. Incubateswere filtered over GF/C glass microfiber filters in a Brandel M-24 CellHarvester. The filters were additionally rinsed with 4 times 2 mL 150 mMK₂HPO₄/10 mM EDTA (pH 7.5, 4° C.). Punched filters were counted inPackard Emulsifier Safe scintillation fluid after 2 hours of extraction.

Representative compounds of the present invention have been shown to beactive in the above affinity testing.

Synthesis and Characterization

The compounds of Formula 8 can be prepared by the methods described byBettina Grahner et al., J. Med. Chem. 1994, 37, 1526-1534 and AngelaStefanachi et al, Tetrahedron Lett. 2003, 44, 2121-2123, as shown abovein Scheme I. Mono-substituted urea 1 reacts with diketene to affordcompound 2, which is cyclized by refluxing in acetic acid to givecompound 3. Compound 4 is prepared by 3-alkylation of compound 3.Nitration of 4 with H₂SO₄/fuming HNO₃ gives compound 5, which iscondensed with 6-chloropyridine-3-carboxaldehyde in ethanol usingpiperidine as the base to give the vinyl compound 6. Compound 6undergoes reductive cyclization in DMF by using SnCl₂ to afford 7, whichcan be further reduced to 8.

As shown above, compound 8 reacts with substituted amine at 160° C. in apressure tube to give compound 9, which can react with acyl chloride toafford compounds of Formula 10. Compound 9 can also react withisocyanate to give compounds of Formula 11.

Proton nuclear magnetic resonance spectroscopy was performed on aVarian-300 MHz spectrometer and spectra were taken in DMSO-d₆. Unlessnoted, chemical shifts are expressed as ppm downfield from relative ppmfrom DMSO (2.5 ppm). Electro-spray-ionization (ESI) mass spectrometrywas performed with a ThermoFinnigan LCQ mass spectrometer.

All compounds were homogeneous as judged using TLC (Silica gel 60 F₂₅₄,0.25 mm, aluminium backed, EM Science, Gibbstown, N.J.) and HPLC(Shimadzu) using Varian C18 5 micron analytical column (4.6 mm×150 mm)in linear gradient solvent system, at a flow rate of 1 mL/min. Thesolvent system used was MeOH (0.1% formic acid):H₂O (0.1% formic acid).Peaks were detected by UV absorption at 300 nm and 254 nm. NMR and massspectra were shown to be consistent with the assigned structure.

1-Propyl-3-(3-oxo-butyryl)-urea (2a)

Diketene (2.6 mL, 33 mmol, reagent stabilized with CuSO₄), was addeddropwise to a stirred solution of n-propylurea (3.06 g, 30 mmol) inpyridine (60 mL) at 0° C. (ice/water bath) under Ar. The resultingdark-yellow solution was stirred at rt for 24 hr. Most of the solventwas evaporated and the solid was collected by filtration and washed withether and dried under vacuum to give the product (4.0 g).

HPLC condition: MeOH 20%-75% gradient in 10 minutes then MeOH 75%.Retention Time=7.00 min. MS: m/z 187 (M+H)⁺.

1-Propyl-6-methyl-uracil (3a)

The acyl urea (2a) (3.2 g) was suspended in acetic acid (30 mL) and themixture was stirred under reflux for 2 hr. Most of the solvent wasevaporated and the solid was stirred with water (20 mL) and filtered togive the product (2.5 g).\

HPLC condition: MeOH 20%-75% gradient in 10 minutes then MeOH 75%.Retention Time=5.72 min. ¹H NMR (DMSO, d₆): 0.87 (t, 3H, J=7.5 Hz), 1.55(m, 2H), 2.23 (s, 3H), 3.65 (t, 2H, J=7.5 Hz), 5.47 (s, 1H), 11.13 (s,1H). ¹³C NMR (DMSO, d₆): 11.61, 11.87, 22.28, 45.55, 101.67, 152.25,154.89, 163.18. MS: m/z 169 (M+H)⁺.

1,3-Dipropyl-6-methyl-uracil (4a)

Method A: 1-Propyl-6-methyluracil (4.5 g) was dissolved in NaOEtsolution (from 850 mg of Na and 60 mL of absolute EtOH) in a pressuretube. After 30 min, n-propyl bromine (5 g) was added. The mixture wasstirred at 85° C. for 24 hr. HPLC indicated that the reaction was only40% complete. More n-propyl bromine (3 g) was added. The mixture wassealed and stirred at 87° C., for another 24 hr. HPLC indicated thatthere was 20% of the starting material left. Additional n-propyl bromine(3 g) was added. The reaction was continued at 87° C. for another 24 h.EtOH was removed and residue was dissolved in water and neutralized with1N HCl and extracted with dichloromethane (DCM). DCM was evaporated andthe crude product was purified by column (43 g silica gel, RTScientific) (CH₂Cl₂:MeOH=100:0 to 98:2).

HPLC condition: MeOH 20%-75% gradient in 10 minutes then MeOH 75%.Retention Time=10.23 min. ¹H NMR (DMSO, d₆): 0.85 (m, 6H), 1.46-1.61 (m,4H), 2.25 (s, 3H), 3.72 (m, 4H), 5.60 (s, 1H). ¹³C NMR (DMSO, d₆):11.61, 11.86, 19.77, 21.15, 22.19, 42.46, 46.59, 100.97, 152.25, 153.28,162.04. MS: m/z 211 (M+H).

Method B: 6-Methyluracil (25.2 g), dry K₂CO₃ (55.2 g) was suspended inDMF (400 mL) in a pressure tube. n-C₃H₇—Br (49 g) was added. The mixturewas stirred at 65-70° C. for 3 days. Solid was removed by filteration.The mother liquid was evaporated, and the residue was purified by columnto give the product (24 g). (170 g silica gel, RT Scientific)(CH₂Cl₂:MeOH=100:0 to 98:2) and byproducts, mixture1-propyl-6-methyluracil (Retention Time=5.82 min) and3-propyl-6-methyluracil (Retention Time=6.65 min) (6.5 g). The producthas a high solubility in ether and can be recrystallised from hexanewhile 1-propyl-6-methyluracil and 3-propyl-6-methyluracil have a lowsolubility in ether.

HPLC condition: MeOH 20%-75% gradient in 10 minutes then MeOH 75%.Retention Time=10.23 min. ¹H NMR (DMSO, d₆): 0.85 (m, 6H), 1.46-1.61 (m,4H), 2.25 (s, 3H), 3.72 (m, 4H), 5.60 (s, 1H). ¹³C NMR (DMSO, d₆):11.61, 11.86, 19.77, 21.15, 22.19, 42.46, 46.59, 100.97, 152.25, 153.28,162.04. MS: m/z 211 (M+H).

1,3-Dipropyl-5-nitro-6-methyl-uracil (5a)

1,3-Dipropyl 6-methyluracil (13.65 g) was added the cold mixture ofH₂SO₄/HNO₃ [concentrated H₂SO₄ (30 mL)+fuming HNO₃ (20 mL)]. The mixturewas stirred at 0-5° C. for 1.5 hr. The mixture was poured into ice andneutralized with saturated NaHCO₃ and extracted with DCM. DCM wasevaporated, and the crude product was purified by column (170 g silicagel, RT Scientific) (CH₂Cl₂:MeOH=100:0 to 99:1) to give the product(yellow oil, 15.3 g).

HPLC condition: MeOH 20%-75% gradient in 10 minutes then MeOH 75%.Retention Time=10.55 min. ¹H NMR (DMSO, d₆): 0.99 (m, 6H), 1.71 (m, 4H),2.52 (s, 3H), 3.92 (m, 4H), 5.60 (s, 1H). ¹³C NMR (DMSO, d₆): 11.65,11.91, 16.24, 20.97, 21.90, 43.88, 47.87, 130.16, 150.33, 151.30,155.52. MS: m/z 256 (M+H).

1,3-Dipropyl-5-nitro-6-(2-(6-chloropyridin-3-yl)vinyl)-uracil (6a)

A mixture of 1,3-dipropyl-5-nitro-6-methyluracil (2.55 g),6-chloropyridine-3-carboxaldehyde (1.60 g), piperidine (1.58 mL), anddry dioxane (50 mL) in a pressure tube was stirred at 110° C. for 23 hr.HPLC indicated only 60% of the starting material was converted to theunsaturated compound [HPLC condition: MeOH 20%-75% gradient in 10minutes then MeOH 75%. Retention Time=12.44 min, MS: m/z 379 (M+H)]. Thesolvent was evaporated, and the residue was purified by column (115 gsilica gel, RT Scientific) (Hexane:Ethyl Acetate=100:0 to 80:20). Thefractions were evaporated and washed with ether to give the product(yellow solid, 600 mg).

HPLC condition: MeOH 20%-75% gradient in 10 minutes then MeOH 75%.Retention Time=12.44 min. ¹H NMR (DMSO, d₆): 0.85 (m, 6H), 1.55-1.65 (m,4H), 3.82 (t, 4H, J=7.5 Hz), 7.07 (d, 1H, J=16.5 Hz), 7.40 (d, 1H,J=16.5 Hz), 7.62 (d, 1H, J=8.7 Hz), 8.24 (dd, J₁=8.7 Hz, J₂=2.4 Hz),8.65 (d, 1H, J=2.4 Hz). ¹³C NMR (DMSO, d₆): 11.66, 11.96, 20.98, 21.93,44.07, 48.59, 118.94, 125.45, 129.43, 130.47, 135.67, 138.60, 149.52,150.11, 150.29, 152.02, 155.82. MS: m/z 379 (M+H).

6-(6-chloropyridin-3-yl)-1,3-dipropyl-5-hydroxy-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione(7a)

The vinyl compound 6a (300 mg), was dissolved in dry DMF (6 mL) in apressure tube. SnCl₂ (1500 mg) was added and the pressure was sealed andstirred at 60° C. for 4 hr. LCMS, indicated the desired7-N-hydroxy-9-deazaxanthine product 7a (rt=9.49 min) and deoxygenatedproduct 8a (rt=10.15, m/z 347). The solvent was evaporated, and theresidue was purified by column (dry loaded, 45 g silica gel, RTScientific) (CH₂Cl₂:MeOH=100:0 to 99:1). The fractions were evaporatedand washed with water and ether to give the mixture of those twoproducts (100 mg).

HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH 95%.Retention Time=9.49 min and 10.15 min.

6-(6-chloropyridin-3-yl)-1,3-dipropyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione(8a)

A mixture of 7a and 8a (100 mg) from last step and SnCl₂ (545 mg) in DMF(5 mL) in a pressure tube was stirred at 164° C. for 24 hr. HPLCindicated the reaction was complete. The solvent was evaporated, and theresidue was stirred with water (20 mL) and filtered. The crude solid waspurified by column (dry loaded, 14 g silica gel, RT Scientific)(CH₂Cl₂:MeOH=100:0 to 99:1). The fractions were evaporated and washedwith ether to give the product.

HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH 95%.Retention Time=10.15 min. ¹H NMR (DMSO, d₆): 0.89 (m, 6H), 1.53-1.72 (m,4H), 3.86 (t, 4H, J=6.9 Hz), 6.95 (s, 1H), 7.61 (d, 1H, J=8.4 Hz), 8.35(dd, J₁=8.4 Hz, J₂=2.4 Hz), 8.96 (d, 1H, J=2.4 Hz). ¹³C NMR (DMSO, d₆):11.78, 11.99, 21.43, 21.73, 42.73, 47.25, 95.17, 112.73, 125.20, 127.20,135.61, 136.11, 136.87, 147.58, 150.13, 151.34, 155.36. MS: m/z 347(M+H).

6-(6-(2-methoxyethylamino)pyridin-3-yl)-1,3-dipropyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione(9a)

8a (100 mg) was suspended in methoxyethylamine (1.5 g), in EtOH (4 mL)in a pressure tube and stirred at 164° C. for 28 hrs. After cooling toroom temperature, the solvent was removed and the solid was purified bycolumn (26 g silica gel, RT Scientific) (CH₂Cl₂:MeOH=100:0 to 97:3). Thefractions were evaporated and washed with ether to give the product 9a(63 mg). The mother liquid was evaporated and afforded another 30 mg ofthe product.

HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH 95%.Retention Time=6.57 min. ¹H NMR (DMSO, d₆): 0.84-0.93 (m, 6H), 1.53-1.71(m, 4H), 3.27 (s, 3H), 3.46 (m, 4H), 3.85 (m, 4H), 6.54 (m, 2H), 6.90(s(br), 1H), 7.86 (dd, 1H, J₁=8.7 Hz, J₂=2.4 Hz), 8.54 (d, 1H, J=2.4Hz), 12.10 (s, 1H). ¹³C NMR (DMSO, d₆): 11.00, 11.20, 20.67, 21.00,40.34, 41.76, 46.33, 57.99, 70.88, 90.94, 108.07, 109.97, 115.14,134.02, 135.83, 138.64, 145.42, 150.69, 154.14, 158.38.

6-(Trifluoromethyl)-N-(5-(2,3,4,5-tetrahydro-2,4-dioxo-1,3-dipropyl-1H-pyrrolo[3,2-d]pyrimidin-6-yl)pyridin-2-yl)-N-(2-methoxyethyl)pyridine-3-carboxamide(10a)

9a (40 mg) was dissolved in pyridine (5 mL) at room temperature.6-(Trifluoromethyl)nicotinoyl chloride (218 mg) was added. The mixturewas stirred at room temperature for 24 h. After quenching with ice, thecrude product was purified by column (26 g silica gel, RT Scientific)(CH₂Cl₂:MeOH=100:0 to 98:2) to give the 10a (43 mg).

HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH 95%.Retention Time=10.21 min. ¹H NMR (DMSO, d₆): 0.83-0.92 (m, 6H),1.53-1.70 (m, 4H), 3.20 (s, 3H), 3.61 (t, 2H, J=5.7 Hz), 3.85 (m, 4H),4.19 (t, 2H, J=5.7 Hz), 6.89 (d, 1H, J=2.4 Hz), 7.41 (d, 1H, J=8.7 Hz),7.84-7.95 (m, 2H), 8.26 (dd, 1H, J₁=8.7 Hz, J₂=2.4 Hz), 8.65 (s, 1H),8.85 (d, 1H, J=2.4 Hz), 12.52 (s, 1H). ¹³C NMR (DMSO, d₆): 10.94, 11.17,20.60, 20.92, 41.91, 46.41, 47.50, 58.09, 69.52, 94.06, 111.75, 120.41,120.86, 123.06, 124.90, 134.74, 135.24, 135.35, 135.74, 137.79, 145.36,146.49, 149.11, 150.56, 154.00, 154.49, 166.80. MS: m/z 559 (M+H)⁺.

6-(6-((Tetrahydrofuran-2-yl)methylamino)pyridin-3-yl)-1,3-dipropyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione(9b)

8a (154 mg) was suspended in tetrahydrofurfurylamine (2.0 g) in EtOH (5ml) in a pressure tube and stirred at 164° C. for 5 days. After coolingto room temperature, the solid was filtered and washed with methanol togive the product (9b) (150 mg).

HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH 95%.Retention Time=7.1 min. ¹H NMR (DMSO, d₆): 0.83-0.93 (m, 6H), 1.53-2.00(m, 8H), 3.40 (m, 2H), 3.59-3.99 (m, 7H), 6.54 (s, 1H), 6.57 (d, 1H,J=8.7 Hz), 6.92 (t, 1H, J=5.4 Hz), 7.85 (dd, 1H, J₁=8.7 Hz, J₂=2.4 Hz),8.52 (d, 1H, J=2.4 Hz), 12.20 (s, 1H). MS: m/z 412(M+H)⁺.

6-(6-(2-(dimethylamino)ethylamino)pyridin-3-yl)-1,3-dipropyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione(9c)

8a (135 mg) was suspended in N,N-dimethylethylenediamine (1.5 g) in EtOH(4 ml) in quartz tube and stirred at 160-175° C. under microwave (400 w)(CEM Mars) for 2 hrs. After cooling to room temperature, the solvent wasremoved and the solid was purified by column (26 g silica gel, RTScientific) (CH₂Cl₂: MeOH=100:0 to 90:10). The fractions was evaporatedand washed with ether to give the product (9c) (90 mg). HPLC condition:MeOH 40%-95% gradient in 10 minutes then MeOH 95%. Retention Time=5.32min. ¹H NMR (DMSO, d₆): 0.83-0.93 (m, 6H), 1.53-1.71 (m, 4H), 2.21 (s,6H), 2.45 (t, 2H, J=6.6 Hz), 3.38 (m, 2H), 3.85 (m, 4H), 6.55 (m, 2H),6.73 (t, 1H, J=5.4 Hz), 7.86 (dd, 1H, J₁=8.7 Hz, J₂=2.4 Hz), 8.54 (d,1H, J=2.4 Hz), 12.22 (s, 1H). MS: m/z 399 (M+H)⁺.

3-(4-fluorophenyl)-1-(5-(2,3,4,5-tetrahydro-2,4-dioxo-1,3-dipropyl-1H-pyrrolo[3,2-d]pyrimidin-6-yl)pyridin-2-yl)-1-(2-methoxyethyl)urea(11a)

9a (25 mg) was suspended in THF (2 ml) in a pressure tube,4-fluorophenyl isocyanate (200 mg) was added and the mixture was stirredat 94° C. for 3 days. After cooling to room temperature, the mixture wasevaporated to almost dry and the solid was filtered and washed withether (two peaks shown in HPLC, rt=8.0 min, rt=11.6 min). The solid wasstirred with DCM, the solid (rt=8.0 min) was removed and the motherliquid was collected. After removal of the solvent, the residue waspurified by column (14 g silica gel, RT Scientific) (CH₂Cl₂: MeOH=100:0to 98:2) to give the product (11a) (9 mg). HPLC condition: MeOH 40%-95%gradient in 10 minutes then MeOH 95%. Retention Time=11.60 min. ¹H NMR(DMSO, d₆): 0.83-0.95 (m, 6H), 1.53-1.75 (m, 4H), 3.26 (s, 3H), 3.60 (t,2H), 3.87 (t, 2H), 4.17 (t, 2H), 6.85 (s, 1H), 7.16 (t, 2H, J=8.7 Hz),7.48 (m, 3H), 8.30 (dd, 1H, J₁=8.7 Hz, J₂=2.4 Hz), 8.95 (d, 1H, J=2.4Hz), 10.87 (s, 1H), 12.50 (s, 1H). MS: m/z 523 (M+H)⁺.

3-(4-fluorophenyl)-1-(5-(2,3,4,5-tetrahydro-2,4-dioxo-1,3-dipropyl-1H-pyrrolo[3,2-d]pyrimidin-6-yl)pyridin-2-yl)-1-((tetrahydrofuran-2-yl)methyl)urea(11b)

9b (30 mg) was suspended in THF (2 ml) in a pressure tube,4-fluorophenyl isocyanate (300 mg) was added and the mixture was stirredat 94° C. for 3 days. After cooling to room temperature, the mixture wasevaporated to almost dry and the solid was filtered, washed with etherand purified by column (14 g silica gel, RT Scientific)(CH₂Cl₂:MeOH=100:0 to 98:2) to give the product (11b) (18 mg). HPLCcondition: MeOH 40%-95% gradient in 10 minutes then MeOH 95%. RetentionTime=11.60 min. ¹H NMR (DMSO, d₆): 0.83-0.95 (m, 6H), 1.53-2.00 (m, 8H),3.60-4.20 (m, 9H), 6.85 (s, 1H), 7.15 (t, 2H, J=8.7 Hz), 7.51 (m, 3H),8.30 (dd, 1H, J₁=8.7 Hz, J₂=2.4 Hz), 8.94 (d, 1H, J=2.4 Hz), 10.69 (s,1H), 12.50 (s, 1H). MS: m/z 549 (M+H)⁺.

1-(2-(dimethylamino)ethyl)-3-(4-fluorophenyl)-1-(5-(2,3,4,5-tetrahydro-2,4-dioxo-1,3-dipropyl-1H-pyrrolo[3,2-d]pyrimidin-6-yl)pyridin-2-yl)urea(11c)

9c (35 mg) was suspended in THF (3 ml) in a pressure tube,4-fluorophenyl isocyanate (130 mg) was added and the mixture was stirredat 85° C. for 3 days. After cooling to room temperature, the mixture wasevaporated and the solid was stirred with ether and filtered The motherliquid contained most of the product. After removal of the solvent, theresidue was purified by column (14 g silica gel, RT Scientific) (CH₂Cl₂:MeOH=100:0 to 95:5) to give the product (11c) (22 mg). HPLC condition:MeOH 40%-95% gradient in 10 minutes then MeOH 95%. Retention Time=7.20min. ¹H NMR (DMSO, d₆): 0.83-0.93 (m, 6H), 1.53-1.71 (m, 4H), 2.28 (s,6H), 2.50 (s, 4H), 3.87 (m, 4H), 4.14 (t, 1H, J=5.4 Hz), 6.83 (s, 1H),7.15 (t, 2H, J=8.7 Hz), 7.52 (m, 3H), 8.24 (dd, 1H, J₁=8.7 Hz, J₂=2.4Hz), 8.92 (d, 1H, J=2.4 Hz), 11.54 (s, 1H). MS: m/z 536 (M+H)⁺.

Representative examples of the present invention are provided below inTables 1-2.

TABLE 1

Ex. # R R¹ R² R³ Y′ 1. H n-propyl n-propyl CH₂OCH₃ H 2. H n-propyln-propyl CH₃ H 3. H n-propyl n-propyl CH₂OH H 4. H n-propyl n-propylCH₂N(CH₃)₂ H 5. H n-propyl n-propyl CH₂-N-piperdinyl H 6. H n-propyln-propyl CH₂-N-morpholinyl H 7. H n-propyl n-propyl cyclopropyl H 8. Hn-propyl n-propyl CH₂-cyclopropyl H 9. H n-propyl n-propyl2-tetrahydrofuranyl H 10. H n-propyl n-propyl CH₂-2-tetrahydrofuran H11. H n-propyl n-propyl 2-tetrahydrothienyl H 12. H n-propyl n-propylCH₂OCH₃ CF₃ 13. H n-propyl n-propyl CH₃ CF₃ 14. H n-propyl n-propylCH₂OH CF₃ 15. H n-propyl n-propyl CH₂N(CH₃)₂ CF₃ 16. H n-propyl n-propylCH₂-N-piperdinyl CF₃ 17. H n-propyl n-propyl CH₂-N-morpholinyl CF₃ 18. Hn-propyl n-propyl cyclopropyl CF₃ 19. H n-propyl n-propylCH₂-cyclopropyl CF₃ 20. H n-propyl n-propyl 2-tetrahydrofuranyl CF₃ 21.H n-propyl n-propyl CH₂-2-tetrahydrofuran CF₃ 22. H n-propyl n-propyl2-tetrahydrothienyl CF₃ 23. H n-propyl n-propyl CH₂OCH₃ F 24. H n-propyln-propyl CH₃ F 25. H n-propyl n-propyl CH₂OH F 26. H n-propyl n-propylCH₂N(CH₃)₂ F 27. H n-propyl n-propyl CH₂-N-piperdinyl F 28. H n-propyln-propyl CH₂-N-morpholinyl F 29. H n-propyl n-propyl cyclopropyl F 30. Hn-propyl n-propyl CH₂-cyclopropyl F 31. H n-propyl n-propyl2-tetrahydrofuranyl F 32. H n-propyl n-propyl CH₂-2-tetrahydrofuran F33. H n-propyl n-propyl 2-tetrahydrothienyl F 34. H n-propyl n-propylCH₂OCH₃ Cl 35. H n-propyl n-propyl CH₃ Cl 36. H n-propyl n-propyl CH₂OHCl 37. H n-propyl n-propyl CH₂N(CH₃)₂ Cl 38. H n-propyl n-propylCH₂-N-piperdinyl Cl 39. H n-propyl n-propyl CH₂-N-morpholinyl Cl 40. Hn-propyl n-propyl cyclopropyl Cl 41. H n-propyl n-propyl CH₂-cyclopropylCl 42. H n-propyl n-propyl 2-tetrahydrofuranyl Cl 43. H n-propyln-propyl CH₂-2-tetrahydrofuran Cl 44. H n-propyl n-propyl2-tetrahydrothienyl Cl 45. H n-propyl n-propyl CH₂OCH₃ Br 46. H n-propyln-propyl CH₃ Br 47. H n-propyl n-propyl CH₂OH Br 48. H n-propyl n-propylCH₂N(CH₃)₂ Br 49. H n-propyl n-propyl CH₂-N-piperdinyl Br 50. H n-propyln-propyl CH₂-N-morpholinyl Br 51. H n-propyl n-propyl cyclopropyl Br 52.H n-propyl n-propyl CH₂-cyclopropyl Br 53. H n-propyl n-propyl2-tetrahydrofuranyl Br 54. H n-propyl n-propyl CH₂-2-tetrahydrofuran Br55. H n-propyl n-propyl 2-tetrahydrothienyl Br 56. H n-propyl n-propylCH₂OCH₃ I 57. H n-propyl n-propyl CH₃ I 58. H n-propyl n-propyl CH₂OH I59. H n-propyl n-propyl CH₂N(CH₃)₂ I 60. H n-propyl n-propylCH₂-N-piperdinyl I 61. H n-propyl n-propyl CH₂-N-morpholinyl I 62. Hn-propyl n-propyl cyclopropyl I 63. H n-propyl n-propyl CH₂-cyclopropylI 64. H n-propyl n-propyl 2-tetrahydrofuranyl I 65. H n-propyl n-propylCH₂-2-tetrahydrofuran I 66. H n-propyl n-propyl 2-tetrahydrothienyl I67. H i-propyl n-propyl CH₂OCH₃ H 68. H i-propyl n-propyl CH₃ H 69. Hi-propyl n-propyl CH₂OH H 70. H i-propyl n-propyl CH₂N(CH₃)₂ H 71. Hi-propyl n-propyl CH₂-N-piperdinyl H 72. H i-propyl n-propylCH₂-N-morpholinyl H 73. H i-propyl n-propyl cyclopropyl H 74. H i-propyln-propyl CH₂-cyclopropyl H 75. H i-propyl n-propyl 2-tetrahydrofuranyl H76. H i-propyl n-propyl CH₂-2-tetrahydrofuran H 77. H i-propyl n-propyl2-tetrahydrothienyl H 78. H i-propyl n-propyl CH₂OCH₃ CF₃ 79. H i-propyln-propyl CH₃ CF₃ 80. H i-propyl n-propyl CH₂OH CF₃ 81. H i-propyln-propyl CH₂N(CH₃)₂ CF₃ 82. H i-propyl n-propyl CH₂-N-piperdinyl CF₃ 83.H i-propyl n-propyl CH₂-N-morpholinyl CF₃ 84. H i-propyl n-propylcyclopropyl CF₃ 85. H i-propyl n-propyl CH₂-cyclopropyl CF₃ 86. Hi-propyl n-propyl 2-tetrahydrofuranyl CF₃ 87. H i-propyl n-propylCH₂-2-tetrahydrofuran CF₃ 88. H i-propyl n-propyl 2-tetrahydrothienylCF₃ 89. H i-propyl n-propyl CH₂OCH₃ F 90. H i-propyl n-propyl CH₃ F 91.H i-propyl n-propyl CH₂OH F 92. H i-propyl n-propyl CH₂N(CH₃)₂ F 93. Hi-propyl n-propyl CH₂-N-piperdinyl F 94. H i-propyl n-propylCH₂-N-morpholinyl F 95. H i-propyl n-propyl cyclopropyl F 96. H i-propyln-propyl CH₂-cyclopropyl F 97. H i-propyl n-propyl 2-tetrahydrofuranyl F98. H i-propyl n-propyl CH₂-2-tetrahydrofuran F 99. H i-propyl n-propyl2-tetrahydrothienyl F 100. H i-propyl n-propyl CH₂OCH₃ Cl 101. Hi-propyl n-propyl CH₃ Cl 102. H i-propyl n-propyl CH₂OH Cl 103. Hi-propyl n-propyl CH₂N(CH₃)₂ Cl 104. H i-propyl n-propylCH₂-N-piperdinyl Cl 105. H i-propyl n-propyl CH₂-N-morpholinyl Cl 106. Hi-propyl n-propyl cyclopropyl Cl 107. H i-propyl n-propylCH₂-cyclopropyl Cl 108. H i-propyl n-propyl 2-tetrahydrofuranyl Cl 109.H i-propyl n-propyl CH₂-2-tetrahydrofuran Cl 110. H i-propyl n-propyl2-tetrahydrothienyl Cl 111. H i-propyl n-propyl CH₂OCH₃ Br 112. Hi-propyl n-propyl CH₃ Br 113. H i-propyl n-propyl CH₂OH Br 114. Hi-propyl n-propyl CH₂N(CH₃)₂ Br 115. H i-propyl n-propylCH₂-N-piperdinyl Br 116. H i-propyl n-propyl CH₂-N-morpholinyl Br 117. Hi-propyl n-propyl cyclopropyl Br 118. H i-propyl n-propylCH₂-cyclopropyl Br 119. H i-propyl n-propyl 2-tetrahydrofuranyl Br 120.H i-propyl n-propyl CH₂-2-tetrahydrofuran Br 121. H i-propyl n-propyl2-tetrahydrothienyl Br 122. H i-propyl n-propyl CH₂OCH₃ I 123. Hi-propyl n-propyl CH₃ I 124. H i-propyl n-propyl CH₂OH I 125. H i-propyln-propyl CH₂N(CH₃)₂ I 126. H i-propyl n-propyl CH₂-N-piperdinyl I 127. Hi-propyl n-propyl CH₂-N-morpholinyl I 128. H i-propyl n-propylcyclopropyl I 129. H i-propyl n-propyl CH₂-cyclopropyl I 130. H i-propyln-propyl 2-tetrahydrofuranyl I 131. H i-propyl n-propylCH₂-2-tetrahydrofuran I 132. H i-propyl n-propyl 2-tetrahydrothienyl I133. H n-butyl n-propyl CH₂OCH₃ H 134. H n-butyl n-propyl CH₃ H 135. Hn-butyl n-propyl CH₂OH H 136. H n-butyl n-propyl CH₂N(CH₃)₂ H 137. Hn-butyl n-propyl CH₂-N-piperdinyl H 138. H n-butyl n-propylCH₂-N-morpholinyl H 139. H n-butyl n-propyl cyclopropyl H 140. H n-butyln-propyl CH₂-cyclopropyl H 141. H n-butyl n-propyl 2-tetrahydrofuranyl H142. H n-butyl n-propyl CH₂-2-tetrahydrofuran H 143. H n-butyl n-propyl2-tetrahydrothienyl H 144. H n-butyl n-propyl CH₂OCH₃ CF₃ 145. H n-butyln-propyl CH₃ CF₃ 146. H n-butyl n-propyl CH₂OH CF₃ 147. H n-butyln-propyl CH₂N(CH₃)₂ CF₃ 148. H n-butyl n-propyl CH₂-N-piperdinyl CF₃149. H n-butyl n-propyl CH₂-N-morpholinyl CF₃ 150. H n-butyl n-propylcyclopropyl CF₃ 151. H n-butyl n-propyl CH₂-cyclopropyl CF₃ 152. Hn-butyl n-propyl 2-tetrahydrofuranyl CF₃ 153. H n-butyl n-propylCH₂-2-tetrahydrofuran CF₃ 154. H n-butyl n-propyl 2-tetrahydrothienylCF₃ 155. H n-butyl n-propyl CH₂OCH₃ F 156. H n-butyl n-propyl CH₃ F 157.H n-butyl n-propyl CH₂OH F 158. H n-butyl n-propyl CH₂N(CH₃)₂ F 159. Hn-butyl n-propyl CH₂-N-piperdinyl F 160. H n-butyl n-propylCH₂-N-morpholinyl F 161. H n-butyl n-propyl cyclopropyl F 162. H n-butyln-propyl CH₂-cyclopropyl F 163. H n-butyl n-propyl 2-tetrahydrofuranyl F164. H n-butyl n-propyl CH₂-2-tetrahydrofuran F 165. H n-butyl n-propyl2-tetrahydrothienyl F 166. H n-butyl n-propyl CH₂OCH₃ Cl 167. H n-butyln-propyl CH₃ Cl 168. H n-butyl n-propyl CH₂OH Cl 169. H n-butyl n-propylCH₂N(CH₃)₂ Cl 170. H n-butyl n-propyl CH₂-N-piperdinyl Cl 171. H n-butyln-propyl CH₂-N-morpholinyl Cl 172. H n-butyl n-propyl cyclopropyl Cl173. H n-butyl n-propyl CH₂-cyclopropyl Cl 174. H n-butyl n-propyl2-tetrahydrofuranyl Cl 175. H n-butyl n-propyl CH₂-2-tetrahydrofuran Cl176. H n-butyl n-propyl 2-tetrahydrothienyl Cl 177. H n-butyl n-propylCH₂OCH₃ Br 178. H n-butyl n-propyl CH₃ Br 179. H n-butyl n-propyl CH₂OHBr 180. H n-butyl n-propyl CH₂N(CH₃)₂ Br 181. H n-butyl n-propylCH₂-N-piperdinyl Br 182. H n-butyl n-propyl CH₂-N-morpholinyl Br 183. Hn-butyl n-propyl cyclopropyl Br 184. H n-butyl n-propyl CH₂-cyclopropylBr 185. H n-butyl n-propyl 2-tetrahydrofuranyl Br 186. H n-butyln-propyl CH₂-2-tetrahydrofuran Br 187. H n-butyl n-propyl2-tetrahydrothienyl Br 188. H n-butyl n-propyl CH₂OCH₃ I 189. H n-butyln-propyl CH₃ I 190. H n-butyl n-propyl CH₂OH I 191. H n-butyl n-propylCH₂N(CH₃)₂ I 192. H n-butyl n-propyl CH₂-N-piperdinyl I 193. H n-butyln-propyl CH₂-N-morpholinyl I 194. H n-butyl n-propyl cyclopropyl I 195.H n-butyl n-propyl CH₂-cyclopropyl I 196. H n-butyl n-propyl2-tetrahydrofuranyl I 197. H n-butyl n-propyl CH₂-2-tetrahydrofuran I198. H n-butyl n-propyl 2-tetrahydrothienyl I 199. H i-butyl n-propylCH₂OCH₃ H 200. H i-butyl n-propyl CH₃ H 201. H i-butyl n-propyl CH₂OH H202. H i-butyl n-propyl CH₂N(CH₃)₂ H 203. H i-butyl n-propylCH₂-N-piperdinyl H 204. H i-butyl n-propyl CH₂-N-morpholinyl H 205. Hi-butyl n-propyl cyclopropyl H 206. H i-butyl n-propyl CH₂-cyclopropyl H207. H i-butyl n-propyl 2-tetrahydrofuranyl H 208. H i-butyl n-propylCH₂-2-tetrahydrofuran H 209. H i-butyl n-propyl 2-tetrahydrothienyl H210. H i-butyl n-propyl CH₂OCH₃ CF₃ 211. H i-butyl n-propyl CH₃ CF₃ 212.H i-butyl n-propyl CH₂OH CF₃ 213. H i-butyl n-propyl CH₂N(CH₃)₂ CF₃ 214.H i-butyl n-propyl CH₂-N-piperdinyl CF₃ 215. H i-butyl n-propylCH₂-N-morpholinyl CF₃ 216. H i-butyl n-propyl cyclopropyl CF₃ 217. Hi-butyl n-propyl CH₂-cyclopropyl CF₃ 218. H i-butyl n-propyl2-tetrahydrofuranyl CF₃ 219. H i-butyl n-propyl CH₂-2-tetrahydrofuranCF₃ 220. H i-butyl n-propyl 2-tetrahydrothienyl CF₃ 221. H i-butyln-propyl CH₂OCH₃ F 222. H i-butyl n-propyl CH₃ F 223. H i-butyl n-propylCH₂OH F 224. H i-butyl n-propyl CH₂N(CH₃)₂ F 225. H i-butyl n-propylCH₂-N-piperdinyl F 226. H i-butyl n-propyl CH₂-N-morpholinyl F 227. Hi-butyl n-propyl cyclopropyl F 228. H i-butyl n-propyl CH₂-cyclopropyl F229. H i-butyl n-propyl 2-tetrahydrofuranyl F 230. H i-butyl n-propylCH₂-2-tetrahydrofuran F 231. H i-butyl n-propyl 2-tetrahydrothienyl F232. H i-butyl n-propyl CH₂OCH₃ Cl 233. H i-butyl n-propyl CH₃ Cl 234. Hi-butyl n-propyl CH₂OH Cl 235. H i-butyl n-propyl CH₂N(CH₃)₂ Cl 236. Hi-butyl n-propyl CH₂-N-piperdinyl Cl 237. H i-butyl n-propylCH₂-N-morpholinyl Cl 238. H i-butyl n-propyl cyclopropyl Cl 239. Hi-butyl n-propyl CH₂-cyclopropyl Cl 240. H i-butyl n-propyl2-tetrahydrofuranyl Cl 241. H i-butyl n-propyl CH₂-2-tetrahydrofuran Cl242. H i-butyl n-propyl 2-tetrahydrothienyl Cl 243. H i-butyl n-propylCH₂OCH₃ Br 244. H i-butyl n-propyl CH₃ Br 245. H i-butyl n-propyl CH₂OHBr 246. H i-butyl n-propyl CH₂N(CH₃)₂ Br 247. H i-butyl n-propylCH₂-N-piperdinyl Br 248. H i-butyl n-propyl CH₂-N-morpholinyl Br 249. Hi-butyl n-propyl cyclopropyl Br 250. H i-butyl n-propyl CH₂-cyclopropylBr 251. H i-butyl n-propyl 2-tetrahydrofuranyl Br 252. H i-butyln-propyl CH₂-2-tetrahydrofuran Br 253. H i-butyl n-propyl2-tetrahydrothienyl Br 254. H i-butyl n-propyl CH₂OCH₃ I 255. H i-butyln-propyl CH₃ I 256. H i-butyl n-propyl CH₂OH I 257. H i-butyl n-propylCH₂N(CH₃)₂ I 258. H i-butyl n-propyl CH₂-N-piperdinyl I 259. H i-butyln-propyl CH₂-N-morpholinyl I 260. H i-butyl n-propyl cyclopropyl I 261.H i-butyl n-propyl CH₂-cyclopropyl I 262. H i-butyl n-propyl2-tetrahydrofuranyl I 263. H i-butyl n-propyl CH₂-2-tetrahydrofuran I264. H i-butyl n-propyl 2-tetrahydrothienyl I 265. H cyclobutyl n-propylCH₂OCH₃ H 266. H cyclobutyl n-propyl CH₃ H 267. H cyclobutyl n-propylCH₂OH H 268. H cyclobutyl n-propyl CH₂N(CH₃)₂ H 269. H cyclobutyln-propyl CH₂-N-piperdinyl H 270. H cyclobutyl n-propyl CH₂-N-morpholinylH 271. H cyclobutyl n-propyl cyclopropyl H 272. H cyclobutyl n-propylCH₂-cyclopropyl H 273. H cyclobutyl n-propyl 2-tetrahydrofuranyl H 274.H cyclobutyl n-propyl CH₂-2-tetrahydrofuran H 275. H cyclobutyl n-propyl2-tetrahydrothienyl H 276. H cyclobutyl n-propyl CH₂OCH₃ CF₃ 277. Hcyclobutyl n-propyl CH₃ CF₃ 278. H cyclobutyl n-propyl CH₂OH CF₃ 279. Hcyclobutyl n-propyl CH₂N(CH₃)₂ CF₃ 280. H cyclobutyl n-propylCH₂-N-piperdinyl CF₃ 281. H cyclobutyl n-propyl CH₂-N-morpholinyl CF₃282. H cyclobutyl n-propyl cyclopropyl CF₃ 283. H cyclobutyl n-propylCH₂-cyclopropyl CF₃ 284. H cyclobutyl n-propyl 2-tetrahydrofuranyl CF₃285. H cyclobutyl n-propyl CH₂-2-tetrahydrofuran CF₃ 286. H cyclobutyln-propyl 2-tetrahydrothienyl CF₃ 287. H cyclobutyl n-propyl CH₂OCH₃ F288. H cyclobutyl n-propyl CH₃ F 289. H cyclobutyl n-propyl CH₂OH F 290.H cyclobutyl n-propyl CH₂N(CH₃)₂ F 291. H cyclobutyl n-propylCH₂-N-piperdinyl F 292. H cyclobutyl n-propyl CH₂-N-morpholinyl F 293. Hcyclobutyl n-propyl cyclopropyl F 294. H cyclobutyl n-propylCH₂-cyclopropyl F 295. H cyclobutyl n-propyl 2-tetrahydrofuranyl F 296.H cyclobutyl n-propyl CH₂-2-tetrahydrofuran F 297. H cyclobutyl n-propyl2-tetrahydrothienyl F 298. H cyclobutyl n-propyl CH₂OCH₃ Cl 299. Hcyclobutyl n-propyl CH₃ Cl 300. H cyclobutyl n-propyl CH₂OH Cl 301. Hcyclobutyl n-propyl CH₂N(CH₃)₂ Cl 302. H cyclobutyl n-propylCH₂-N-piperdinyl Cl 303. H cyclobutyl n-propyl CH₂-N-morpholinyl Cl 304.H cyclobutyl n-propyl cyclopropyl Cl 305. H cyclobutyl n-propylCH₂-cyclopropyl Cl 306. H cyclobutyl n-propyl 2-tetrahydrofuranyl Cl307. H cyclobutyl n-propyl CH₂-2-tetrahydrofuran Cl 308. H cyclobutyln-propyl 2-tetrahydrothienyl Cl 309. H cyclobutyl n-propyl CH₂OCH₃ Br310. H cyclobutyl n-propyl CH₃ Br 311. H cyclobutyl n-propyl CH₂OH Br312. H cyclobutyl n-propyl CH₂N(CH₃)₂ Br 313. H cyclobutyl n-propylCH₂-N-piperdinyl Br 314. H cyclobutyl n-propyl CH₂-N-morpholinyl Br 315.H cyclobutyl n-propyl cyclopropyl Br 316. H cyclobutyl n-propylCH₂-cyclopropyl Br 317. H cyclobutyl n-propyl 2-tetrahydrofuranyl Br318. H cyclobutyl n-propyl CH₂-2-tetrahydrofuran Br 319. H cyclobutyln-propyl 2-tetrahydrothienyl Br 320. H cyclobutyl n-propyl CH₂OCH₃ I321. H cyclobutyl n-propyl CH₃ I 322. H cyclobutyl n-propyl CH₂OH I 323.H cyclobutyl n-propyl CH₂N(CH₃)₂ I 324. H cyclobutyl n-propylCH₂-N-piperdinyl I 325. H cyclobutyl n-propyl CH₂-N-morpholinyl I 326. Hcyclobutyl n-propyl cyclopropyl I 327. H cyclobutyl n-propylCH₂-cyclopropyl I 328. H cyclobutyl n-propyl 2-tetrahydrofuranyl I 329.H cyclobutyl n-propyl CH₂-2-tetrahydrofuran I 330. H cyclobutyl n-propyl2-tetrahydrothienyl I 331. H cyclopropyl- n-propyl CH₂OCH₃ H methyl-332. H cyclopropyl- n-propyl CH₃ H methyl- 333. H cyclopropyl- n-propylCH₂OH H methyl- 334. H cyclopropyl- n-propyl CH₂N(CH₃)₂ H methyl- 335. Hcyclopropyl- n-propyl CH₂-N-piperdinyl H methyl- 336. H cyclopropyl-n-propyl CH₂-N-morpholinyl H methyl- 337. H cyclopropyl- n-propylcyclopropyl H methyl- 338. H cyclopropyl- n-propyl CH₂-cyclopropyl Hmethyl- 339. H cyclopropyl- n-propyl 2-tetrahydrofuranyl H methyl- 340.H cyclopropyl- n-propyl CH₂-2-tetrahydrofuran H methyl- 341. Hcyclopropyl- n-propyl 2-tetrahydrothienyl H methyl- 342. H cyclopropyl-n-propyl CH₂OCH₃ CF₃ methyl- 343. H cyclopropyl- n-propyl CH₃ CF₃methyl- 344. H cyclopropyl- n-propyl CH₂OH CF₃ methyl- 345. Hcyclopropyl- n-propyl CH₂N(CH₃)₂ CF₃ methyl- 346. H cyclopropyl-n-propyl CH₂-N-piperdinyl CF₃ methyl- 347. H cyclopropyl- n-propylCH₂-N-morpholinyl CF₃ methyl- 348. H cyclopropyl- n-propyl cyclopropylCF₃ methyl- 349. H cyclopropyl- n-propyl CH₂-cyclopropyl CF₃ methyl-350. H cyclopropyl- n-propyl 2-tetrahydrofuranyl CF₃ methyl- 351. Hcyclopropyl- n-propyl CH₂-2-tetrahydrofuran CF₃ methyl- 352. Hcyclopropyl- n-propyl 2-tetrahydrothienyl CF₃ methyl- 353. Hcyclopropyl- n-propyl CH₂OCH₃ F methyl- 354. H cyclopropyl- n-propyl CH₃F methyl- 355. H cyclopropyl- n-propyl CH₂OH F methyl- 356. Hcyclopropyl- n-propyl CH₂N(CH₃)₂ F methyl- 357. H cyclopropyl- n-propylCH₂-N-piperdinyl F methyl- 358. H cyclopropyl- n-propylCH₂-N-morpholinyl F methyl- 359. H cyclopropyl- n-propyl cyclopropyl Fmethyl- 360. H cyclopropyl- n-propyl CH₂-cyclopropyl F methyl- 361. Hcyclopropyl- n-propyl 2-tetrahydrofuranyl F methyl- 362. H cyclopropyl-n-propyl CH₂-2-tetrahydrofuran F methyl- 363. H cyclopropyl- n-propyl2-tetrahydrothienyl F methyl- 364. H cyclopropyl- n-propyl CH₂OCH₃ Clmethyl- 365. H cyclopropyl- n-propyl CH₃ Cl methyl- 366. H cyclopropyl-n-propyl CH₂OH Cl methyl- 367. H cyclopropyl- n-propyl CH₂N(CH₃)₂ Clmethyl- 368. H cyclopropyl- n-propyl CH₂-N-piperdinyl Cl methyl- 369. Hcyclopropyl- n-propyl CH₂-N-morpholinyl Cl methyl- 370. H cyclopropyl-n-propyl cyclopropyl Cl methyl- 371. H cyclopropyl- n-propylCH₂-cyclopropyl Cl methyl- 372. H cyclopropyl- n-propyl2-tetrahydrofuranyl Cl methyl- 373. H cyclopropyl- n-propylCH₂-2-tetrahydrofuran Cl methyl- 374. H cyclopropyl- n-propyl2-tetrahydrothienyl Cl methyl- 375. H cyclopropyl- n-propyl CH₂OCH₃ Brmethyl- 376. H cyclopropyl- n-propyl CH₃ Br methyl- 377. H cyclopropyl-n-propyl CH₂OH Br methyl- 378. H cyclopropyl- n-propyl CH₂N(CH₃)₂ Brmethyl- 379. H cyclopropyl- n-propyl CH₂-N-piperdinyl Br methyl- 380. Hcyclopropyl- n-propyl CH₂-N-morpholinyl Br methyl- 381. H cyclopropyl-n-propyl cyclopropyl Br methyl- 382. H cyclopropyl- n-propylCH₂-cyclopropyl Br methyl- 383. H cyclopropyl- n-propyl2-tetrahydrofuranyl Br methyl- 384. H cyclopropyl- n-propylCH₂-2-tetrahydrofuran Br methyl- 385. H cyclopropyl- n-propyl2-tetrahydrothienyl Br methyl- 386. H cyclopropyl- n-propyl CH₂OCH₃ Imethyl- 387. H cyclopropyl- n-propyl CH₃ I methyl- 388. H cyclopropyl-n-propyl CH₂OH I methyl- 389. H cyclopropyl- n-propyl CH₂N(CH₃)₂ Imethyl- 390. H cyclopropyl- n-propyl CH₂-N-piperdinyl I methyl- 391. Hcyclopropyl- n-propyl CH₂-N-morpholinyl I methyl- 392. H cyclopropyl-n-propyl cyclopropyl I methyl- 393. H cyclopropyl- n-propylCH₂-cyclopropyl I methyl- 394. H cyclopropyl- n-propyl2-tetrahydrofuranyl I methyl- 395. H cyclopropyl- n-propylCH₂-2-tetrahydrofuran I methyl- 396. H cyclopropyl- n-propyl2-tetrahydrothienyl I methyl-

TABLE 2

Examples 1-396 of Table 2 correspond to Examples 1-396 of Table 1.

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise that as specifically described herein.

1. A compound of formula I or a stereoisomer or a pharmaceuticallyacceptable salt thereof:

wherein: R is selected from: H, OH, C₁₋₆ alkyl, halo-C₁₋₈ alkyl, C₃₋₆alkenyl, C₃₋₆ alkynyl, (C₃₋₈ cycloalkyl)C₁₋₈ alkylene, (C₄₋₁₀heterocycle)C₁₋₈ alkylene, (C₆₋₁₀ aryl)C₁₋₈ alkylene, and (C₅₋₁₀heteroaryl)C₁₋₈ alkylene, wherein R optionally is substituted with 1R^(d); R^(d) is independently selected from: F, Cl, Br, I, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, OC₁₋₆ alkyl, NO₂, —CN, CF₃, and OCF₃; R¹ andR² are independently selected from: H, C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈alkynyl, C₁₋₈ alkoxy, C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₈ alkylene,C₄₋₁₀ heterocycle, (C₄₋₁₀ heterocycle)C₁₋₈ alkylene, C₆₋₁₀ aryl, (C₆₋₁₀aryl)C₁₋₈ alkylene, C₅₋₁₀ heteroaryl, and (C₅₋₁₀ heteroaryl)C₁₋₈alkylene, wherein R¹ and R² are independently optionally substitutedwith 1-2 R^(1a); R^(1a) is independently selected from: F, Cl, Br, I,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(a)OR^(a),—(CH₂)_(a)NR^(a)R^(a), —(CH₂)_(a)NHOH, —(CH₂)_(a)NR^(a)NR^(a)R^(a),—(CH₂)_(a)NO₂, —(CH₂)_(a)CN, —(CH₂)_(a)CO₂R^(a), —(CH₂)_(a)C(O)R^(a),—(CH₂)_(a)OC(O)R^(a), —(CH₂)_(a)CONR^(a)R^(a), CF₃, and OCF₃; R^(a) isindependently selected from: H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₈ alkylene, C₄₋₁₀ heterocycle,(C₄₋₁₀ heterocycle)C₁₋₈ alkylene, C₆₋₁₀ aryl, (C₆₋₁₀ aryl)C₁₋₈ alkylene,C₅₋₁₀ heteroaryl, and (C₅₋₁₀ heteroaryl)C₁₋₈ alkylene, wherein the alkylis optionally interrupted with 1-2 heteroatoms selected from the groupconsisting of —O—, —S(O)_(p)— and —NR^(b)—; R^(b) is independentlyselected from the group consisting of H, C₁₋₆ alkyl, and benzyl; R³ isselected from: OH, C₁₋₈ alkoxy, NR^(3a)R^(3b), C₃₋₈ cycloalkyl, C₄₋₁₀heterocycle, C₆₋₁₀ aryl, and C₅₋₁₀ heteroaryl, wherein the cycloalkyl,heterocycle, aryl, and heteroaryl are optionally substituted with 1-2R^(3c); R^(3a) and R^(3b) are independently selected from: C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, phenyl, and benzyl; R^(3c) is independentlyselected from: F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,—(CH₂)_(a)OR^(a), —(CH₂)_(a)NR^(a)R^(a), —(CH₂)_(a)NHOH,—(CH₂)_(a)NR^(a)NR^(a)R^(a), —(CH₂)_(a)NO₂, —(CH₂)_(a)CN,—(CH₂)_(a)CO₂R^(a), —(CH₂)_(a)C(O)R^(a), —(CH₂)_(a)OC(O)R^(a),—(CH₂)_(a)CONR^(a)R^(a), CF₃, and OCF₃; X is selected from: (CH₂)_(q),(CH₂)_(r)C(O), and (CH₂)_(r)C(O)NR⁴; R⁴ is selected from: H, C₁₋₄ alkyl,C₁₋₄ alkoxy, and C₁₋₄ haloalkyl; Y is selected from: 5-10 memberedheteroaryl and 6-10 membered aryl, wherein Y is optionally substitutedwith 1-4 Y¹; Y¹ is independently selected from: F, Cl, Br, I, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(a)OR^(a),—(CH₂)_(a)NR^(a)R^(a), —(CH₂)_(a)NHOH, —(CH₂)_(a)NR^(a)NR^(a)R^(a),—(CH₂)_(a)NO₂, —(CH₂)_(a)CN, —(CH₂)_(a)CO₂R^(a), —(CH₂)_(a)C(O)R^(a),—(CH₂)_(a)OC(O)R^(a), —(CH₂)_(a)CONR^(a)R^(a), CF₃, and OCF₃; a isindependently selected from the group consisting of 0, 1, and 2; n isindependently selected from: 1, 2, and 3; p is independently selectedfrom: 0, 1, and 2; q is independently selected from 1, 2, 3, and 4; and,r is independently selected from 0, 1, 2, and
 3. 2. The compoundaccording to claim 1, wherein the compound is of formula II or astereoisomer or a pharmaceutically acceptable salt thereof:

wherein: R is selected from: H and C₁₋₄ alkyl; R¹ and R² areindependently selected from: H, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl,C₃₋₆ cycloalkyl, (C₃₋₆ cycloalkyl)C₁₋₂ alkylene, C₅₋₆ heterocycle, (C₅₋₆heterocycle)C₁₋₂ alkylene, C₆₋₁₀ aryl, (C₆₋₁₀ aryl)C₁₋₂ alkylene, C₅₋₁₀heteroaryl, and (C₅₋₁₀ heteroaryl)C₁₋₂ alkylene, wherein R¹ and R² areindependently optionally substituted with 1-2 R^(1a); R^(1a) isindependently selected from: F, Cl, Br, I, C₁₋₄ alkyl, OR^(a),NR^(a)R^(a), NO₂, —CN, CO₂R^(a), C(O)R^(a), OC(O)R^(a), CONR^(a)R^(a),CF₃, and OCF₃; R³ is selected from: OCH₃, OCH₂CH₃, NR^(3a)R^(3b), C₃₋₆cycloalkyl, and C₅₋₆ heterocycle, wherein the cycloalkyl and heterocycleare optionally substituted with 1-2 R^(3c); R^(3a) and R^(3b) areindependently selected from: C₁₋₄ alkyl, phenyl, and benzyl; R^(3c) isindependently selected from: F, Cl, Br, I, C₁₋₄ alkyl, OR^(a),NR^(a)R^(a), NO₂, —CN, CO₂R^(a), C(O)R^(a), OC(O)R^(a), CONR^(a)R^(a),CF₃, and OCF₃; Y is selected from: 5-6 membered heteroaryl and phenyl,wherein Y is optionally substituted with 1-2 Y¹; Y¹ is independentlyselected from: F, Cl, Br, I, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,OR^(a), NR^(a)R^(a), NO₂, —CN, CO₂R^(a), C(O)R^(a), OC(O)R^(a),CONR^(a)R^(a), CF₃, and OCF₃; and, R^(a) is independently selected from:H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl, and benzyl.
 3. The compoundaccording to claim 2, wherein: R is H; R¹ and R² are independentlyselected from: n-propyl, cyclopropylmethyl, and cyclobutyl; R³ isselected from: cyclopropyl, cyclobutyl, N-pyrrolidino, N-piperidino,N-piperazino, and N-morpholino; Y is selected from: pyridyl andpyrimidyl, wherein Y is optionally substituted with 1-2 Y¹; and, Y¹ isindependently selected from: F, Cl, CH₃, OCH₃, NO₂, —CN, and CF₃.
 4. Thecompound according to claim 3, wherein: R¹ is selected from: n-propyland cyclopropylmethyl; and, R² is n-propyl.
 5. The compound according toclaim 3, wherein: R¹ is n-propyl; and, R² is n-propyl.
 6. The compoundaccording to claim 1, wherein the compound is of formula IV or astereoisomer or a pharmaceutically acceptable salt thereof:

wherein: R is selected from: H and C₁₋₄ alkyl; R¹ and R² areindependently selected from: H, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl,C₃₋₆ cycloalkyl, (C₃₋₆ cycloalkyl)C₁₋₂ alkylene, C₅₋₆ heterocycle, (C₅₋₆heterocycle)C₁₋₂ alkylene, C₆₋₁₀ aryl, (C₆₋₁₀ aryl)C₁₋₂ alkylene, C₅₋₁₀heteroaryl, and (C₅₋₁₀ heteroaryl)C₁₋₂ alkylene, wherein R¹ and R² areindependently optionally substituted with 1-2 R^(1a); R^(1a) isindependently selected from: F, Cl, Br, I, C₁₋₄ alkyl, OR^(a),NR^(a)R^(a), NO₂, —CN, CO₂R^(a), C(O)R^(a), OC(O)R^(a), CONR^(a)R^(a),CF₃, and OCF₃; R³ is selected from: OCH₃, OCH₂CH₃, NR^(3a)R^(3b), C₃₋₆cycloalkyl, and C₅₋₆ heterocycle, wherein the cycloalkyl and heterocycleare optionally substituted with 1-2 R^(3c); R^(3a) and R^(3b) areindependently selected from: C₁₋₄ alkyl, phenyl, and benzyl; R^(3c) isindependently selected from: F, Cl, Br, I, C₁₋₄ alkyl, OR^(a),NR^(a)R^(a), NO₂, —CN, CO₂R^(a), C(O)R^(a), OC(O)R^(a), CONR^(a)R^(a),CF₃, and OCF₃; Y is selected from: 5-6 membered heteroaryl and phenyl,wherein Y is optionally substituted with 1-2 Y¹; Y¹ is independentlyselected from: F, Cl, Br, I, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,OR^(a), NR^(a)R^(a), NO₂, —CN, CO₂R^(a), C(O)R^(a), OC(O)R^(a),CONR^(a)R^(a), CF₃, and OCF₃; and, R^(a) is independently selected from:H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl, and benzyl.
 7. The compoundaccording to claim 1, wherein the compound is of formula V or VI orstereoisomer or a pharmaceutically acceptable salt thereof:


8. The compound according to claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 9. The compound accordingto claim 1, wherein the compound is selected from

Ex. # R R¹ R² R³ Y′
 1. H n-propyl n-propyl CH₂OCH₃ H
 2. H n-propyln-propyl CH₃ H
 3. H n-propyl n-propyl CH₂OH H
 4. H n-propyl n-propylCH₂N(CH₃)₂ H
 5. H n-propyl n-propyl CH₂—N-piperdinyl H
 6. H n-propyln-propyl CH₂—N- H morpholinyl
 7. H n-propyl n-propyl cyclopropyl H
 8. Hn-propyl n-propyl CH₂-cyclopropyl H
 9. H n-propyl n-propyl2-tetrahydrofuranyl H
 10. H n-propyl n-propyl CH₂-2-tetra- H hydrofuran11. H n-propyl n-propyl 2-tetrahydrothienyl H
 12. H n-propyl n-propylCH₂OCH₃ CF₃
 13. H n-propyl n-propyl CH₃ CF₃
 14. H n-propyl n-propylCH₂OH CF₃
 15. H n-propyl n-propyl CH₂N(CH₃)₂ CF₃
 16. H n-propyl n-propylCH₂—N-piperdinyl CF₃
 17. H n-propyl n-propyl CH₂—N- CF₃ morpholinyl 18.H n propyl n-propyl cyclopropyl CF₃
 19. H n-propyl n-propylCH₂-cyclopropyl CF₃
 20. H n-propyl n-propyl 2-tetrahydrofuranyl CF₃ 21.H n-propyl n-propyl CH₂-2-tetra- CF₃ hydrofuran
 22. H n-propyl n-propyl2-tetrahydrothienyl CF₃
 23. H n-propyl n-propyl CH₂OCH₃ F
 24. H n-propyln-propyl CH₃ F
 25. H n-propyl n-propyl CH₂OH F
 26. H n-propyl n-propylCH₂N(CH₃)₂ F
 27. H n-propyl n-propyl CH₂—N-piperdinyl F
 28. H n-propyln-propyl CH₂—N- F morpholinyl
 29. H n-propyl n-propyl cyclopropyl F 30.H n-propyl n-propyl CH₂-cyclopropyl F
 31. H n-propyl n-propyl2-tetrahydrofuranyl F
 32. H n-propyl n-propyl CH₂-2-tetra- F hydrofuran33. H n-propyl n-propyl 2-tetrahydrothienyl F
 34. H n-propyl n-propylCH₂OCH₃ Cl
 35. H n-propyl n-propyl CH₃ Cl
 36. H n-propyl n-propyl CH₂OHCl
 37. H n-propyl n-propyl CH₂N(CH₃)₂ Cl
 38. H n-propyl n-propylCH₂—N-piperdinyl Cl
 39. H n-propyl n-propyl CH₂—N- Cl morpholinyl
 40. Hn-propyl n-propyl cyclopropyl Cl
 41. H n-propyl n-propyl CH₂-cyclopropylCl
 42. H n-propyl n-propyl 2-tetrahydrofuranyl Cl
 43. H n-propyln-propyl CH₂-2-tetra- Cl hydrofuran
 44. H n-propyl n-propyl2-tetrahydrothienyl Cl
 45. H n-propyl n-propyl CH₂OCH₃ Br
 46. H n-propyln-propyl CH₃ Br
 47. H n-propyl n-propyl CH₂OH Br
 48. H n-propyl n-propylCH₂N(CH₃)₂ Br
 49. H n-propyl n-propyl CH₂—N-piperdinyl Br
 50. H n-propyln-propyl CH₂—N- Br morpholinyl
 51. H n-propyl n-propyl cyclopropyl Br52. H n-propyl n-propyl CH₂-cyclopropyl Br
 53. H n-propyl n-propyl2-tetrahydrofuranyl Br
 54. H n-propyl n-propyl CH₂-2-tetra- Brhydrofuran
 55. H n-propyl n-propyl 2-tetrahydrothienyl Br
 56. H n-propyln-propyl CH₂OCH₃ I
 57. H n-propyl n-propyl CH₃ I
 58. H n-propyl n-propylCH₂OH I
 59. H n-propyl n-propyl CH₂N(CH₃)₂ I
 60. H n-propyl n-propylCH₂—N-piperdinyl I
 61. H n-propyl n-propyl CH₂—N- I morpholinyl
 62. Hn-propyl n-propyl cyclopropyl I
 63. H n-propyl n-propyl CH₂-cyclopropylI
 64. H n-propyl n-propyl 2-tetrahydrofuranyl I
 65. H n-propyl n-propylCH₂-2-tetra- I hydrofuran
 66. H n-propyl n-propyl 2-tetrahydrothienyl I67. H i-propyl n-propyl CH₂OCH₃ H
 68. H i-propyl n-propyl CH₃ H
 69. Hi-propyl n-propyl CH₂OH H
 70. H i-propyl n-propyl CH₂N(CH₃)₂ H
 71. Hi-propyl n-propyl CH₂—N-piperdinyl H
 72. H i-propyl n-propyl CH₂—N- Hmorpholinyl
 73. H i-propyl n-propyl cyclopropyl H
 74. H i-propyln-propyl CH₂-cyclopropyl H
 75. H i-propyl n-propyl 2-tetrahydrofuranyl H76. H i-propyl n-propyl CH₂-2-tetra- H hydrofuran
 77. H i-propyln-propyl 2-tetrahydrothienyl H
 78. H i-propyl n-propyl CH₂OCH₃ CF₃
 79. Hi-propyl n-propyl CH₃ CF₃
 80. H i-propyl n-propyl CH₂OH CF₃
 81. Hi-propyl n-propyl CH₂N(CH₃)₂ CF₃
 82. H i-propyl n-propylCH₂—N-piperdinyl CF₃
 83. H i-propyl n-propyl CH₂—N- CF₃ morpholinyl 84.H i-propyl n-propyl cyclopropyl CF₃
 85. H i-propyl n-propylCH₂-cyclopropyl CF₃
 86. H i-propyl n-propyl 2-tetrahydrofuranyl CF₃ 87.H i-propyl n-propyl CH₂-2-tetra- CF₃ hydrofuran
 88. H i-propyl n-propyl2-tetrahydrothienyl CF₃
 89. H i-propyl n-propyl CH₂OCH₃ F
 90. H i-propyln-propyl CH₃ F
 91. H i-propyl n-propyl CH₂OH F
 92. H i-propyl n-propylCH₂N(CH₃)₂ F
 93. H i-propyl n-propyl CH₂—N-piperdinyl F
 94. H i-propyln-propyl CH₂—N- F morpholinyl
 95. H i-propyl n-propyl cyclopropyl F 96.H i-propyl n-propyl CH₂-cyclopropyl F
 97. H i-propyl n-propyl2-tetrahydrofuranyl F
 98. H i-propyl n-propyl CH₂-2-tetra- F hydrofuran99. H i-propyl n-propyl 2-tetrahydrothienyl F
 100. H i-propyl n-propylCH₂OCH₃ Cl
 101. H i-propyl n-propyl CH₃ Cl
 102. H i-propyl n-propylCH₂OH Cl
 103. H i-propyl n-propyl CH₂N(CH₃)₂ Cl
 104. H i-propyl n-propylCH₂—N-piperdinyl Cl
 105. H i-propyl n-propyl CH₂—N- Cl morpholinyl 106.H i-propyl n-propyl cyclopropyl Cl
 107. H i-propyl n-propylCH₂-cyclopropyl Cl
 108. H i-propyl n-propyl 2-tetrahydrofuranyl Cl 109.H i-propyl n-propyl CH₂-2-tetra- Cl hydrofuran
 110. H i-propyl n-propyl2-tetrahydrothienyl Cl
 111. H i-propyl n-propyl CH₂OCH₃ Br
 112. Hi-propyl n-propyl CH₃ Br
 113. H i-propyl n-propyl CH₂OH Br
 114. Hi-propyl n-propyl CH₂N(CH₃)₂ Br
 115. H i-propyl n-propylCH₂—N-piperdinyl Br
 116. H i-propyl n-propyl CH₂—N- Br morpholinyl 117.H i-propyl n-propyl cyclopropyl Br
 118. H i-propyl n-propylCH₂-cyclopropyl Br
 119. H i-propyl n-propyl 2-tetrahydrofuranyl Br 120.H i-propyl n-propyl CH₂-2-tetra- Br hydrofuran
 121. H i-propyl n-propyl2-tetrahydrothienyl Br
 122. H i-propyl n-propyl CH₂OCH₃ I
 123. Hi-propyl n-propyl CH₃ I
 124. H i-propyl n-propyl CH₂OH I
 125. H i-propyln-propyl CH₂N(CH₃)₂ I
 126. H i-propyl n-propyl CH₂—N-piperdinyl I
 127. Hi-propyl n-propyl CH₂—N- I morpholinyl
 128. H i-propyl n-propylcyclopropyl I
 129. H i-propyl n-propyl CH₂-cyclopropyl I
 130. H i-propyln-propyl 2-tetrahydrofuranyl I
 131. H i-propyl n-propyl CH₂-2-tetra- Ihydrofuran
 132. H i-propyl n-propyl 2-tetrahydrothienyl I
 133. H n-butyln-propyl CH₂OCH₃ H
 134. H n-butyl n-propyl CH₃ H
 135. H n-butyl n-propylCH₂OH H
 136. H n-butyl n-propyl CH₂N(CH₃)₂ H
 137. H n-butyl n-propylCH₂—N-piperdinyl H
 138. H n-butyl n-propyl CH₂—N- H morpholinyl
 139. Hn-butyl n-propyl cyclopropyl H
 140. H n-butyl n-propyl CH₂-cyclopropyl H141. H n-butyl n-propyl 2-tetrahydrofuranyl H
 142. H n-butyl n-propylCH₂-2-tetra- H hydrofuran
 143. H n-butyl n-propyl 2-tetrahydrothienyl H144. H n-butyl n-propyl CH₂OCH₃ CF₃
 145. H n-butyl n-propyl CH₃ CF₃ 146.H n-butyl n-propyl CH₂OH CF₃
 147. H n-butyl n-propyl CH₂N(CH₃)₂ CF₃ 148.H n-butyl n-propyl CH₂—N-piperdinyl CF₃
 149. H n-butyl n-propyl CH₂—N-CF₃ morpholinyl
 150. H n-butyl n-propyl cyclopropyl CF₃
 151. H n-butyln-propyl CH₂-cyclopropyl CF₃
 152. H n-butyl n-propyl 2-tetrahydrofuranylCF₃
 153. H n-butyl n-propyl CH₂-2-tetra- CF₃ hydrofuran
 154. H n-butyln-propyl 2-tetrahydrothienyl CF₃
 155. H n-butyl n-propyl CH₂OCH₃ F 156.H n-butyl n-propyl CH₃ F
 157. H n-butyl n-propyl CH₂OH F
 158. H n-butyln-propyl CH₂N(CH₃)₂ F
 159. H n-butyl n-propyl CH₂—N-piperdinyl F
 160. Hn-butyl n-propyl CH₂—N- F morpholinyl
 161. H n-butyl n-propylcyclopropyl F
 162. H n-butyl n-propyl CH₂-cyclopropyl F
 163. H n-butyln-propyl 2-tetrahydrofuranyl F
 164. H n-butyl n-propyl CH₂-2-tetra- Fhydrofuran
 165. H n-butyl n-propyl 2-tetrahydrothienyl F
 166. H n-butyln-propyl CH₂OCH₃ Cl
 167. H n-butyl n-propyl CH₃ Cl
 168. H n-butyln-propyl CH₂OH Cl
 169. H n-butyl n-propyl CH₂N(CH₃)₂ Cl
 170. H n-butyln-propyl CH₂—N-piperdinyl Cl
 171. H n-butyl n-propyl CH₂—N- Clmorpholinyl
 172. H n-butyl n-propyl cyclopropyl Cl
 173. H n-butyln-propyl CH₂-cyclopropyl Cl
 174. H n-butyl n-propyl 2-tetrahydrofuranylCl
 175. H n-butyl n-propyl CH₂-2-tetra- Cl hydrofuran
 176. H n-butyln-propyl 2-tetrahydrothienyl Cl
 177. H n-butyl n-propyl CH₂OCH₃ Br 178.H n-butyl n-propyl CH₃ Br
 179. H n-butyl n-propyl CH₂OH Br
 180. Hn-butyl n-propyl CH₂N(CH₃)₂ Br
 181. H n-butyl n-propyl CH₂—N-piperdinylBr
 182. H n-butyl n-propyl CH₂—N- Br morpholinyl
 183. H n-butyl n-propylcyclopropyl Br
 184. H n-butyl n-propyl CH₂-cyclopropyl Br
 185. H n-butyln-propyl 2-tetrahydrofuranyl Br
 186. H n-butyl n-propyl CH₂-2-tetra- Brhydrofuran
 187. H n-butyl n-propyl 2-tetrahydrothienyl Br
 188. H n-butyln-propyl CH₂OCH₃ I
 189. H n-butyl n-propyl CH₃ I
 190. H n-butyl n-propylCH₂OH I
 191. H n-butyl n-propyl CH₂N(CH₃)₂ I
 192. H n-butyl n-propylCH₂—N-piperdinyl I
 193. H n-butyl n-propyl CH₂—N- I morpholinyl
 194. Hn-butyl n-propyl cyclopropyl I
 195. H n-butyl n-propyl CH₂-cyclopropyl I196. H n-butyl n-propyl 2-tetrahydrofuranyl I
 197. H n-butyl n-propylCH₂-2-tetra- I hydrofuran
 198. H n-butyl n-propyl 2-tetrahydrothienyl I199. H i-butyl n-propyl CH₂OCH₃ H
 200. H i-butyl n-propyl CH₃ H
 201. Hi-butyl n-propyl CH₂OH H
 202. H i-butyl n-propyl CH₂N(CH₃)₂ H
 203. Hi-butyl n-propyl CH₂—N-piperdinyl H
 204. H i-butyl n-propyl CH₂—N- Hmorpholinyl
 205. H i-butyl n-propyl cyclopropyl H
 206. H i-butyln-propyl CH₂-cyclopropyl H
 207. H i-butyl n-propyl 2-tetrahydrofuranyl H208. H i-butyl n-propyl CH₂-2-tetra- H hydrofuran
 209. H i-butyln-propyl 2-tetrahydrothienyl H
 210. H i-butyl n-propyl CH₂OCH₃ CF₃ 211.H i-butyl n-propyl CH₃ CF₃
 212. H i-butyl n-propyl CH₂OH CF₃
 213. Hi-butyl n-propyl CH₂N(CH₃)₂ CF₃
 214. H i-butyl n-propyl CH₂—N-piperdinylCF₃
 215. H i-butyl n-propyl CH₂—N- CF₃ morpholinyl
 216. H i-butyln-propyl cyclopropyl CF₃
 217. H i-butyl n-propyl CH₂-cyclopropyl CF₃218. H i-butyl n-propyl 2-tetrahydrofuranyl CF₃
 219. H i-butyl n-propylCH₂-2-tetra- CF₃ hydrofuran
 220. H i-butyl n-propyl 2-tetrahydrothienylCF₃
 221. H i-butyl n-propyl CH₂OCH₃ F
 222. H i-butyl n-propyl CH₃ F 223.H i-butyl n-propyl CH₂OH F
 224. H i-butyl n-propyl CH₂N(CH₃)₂ F
 225. Hi-butyl n-propyl CH₂—N-piperdinyl F
 226. H i-butyl n-propyl CH₂—N- Fmorpholinyl
 227. H i-butyl n-propyl cyclopropyl F
 228. H i-butyln-propyl CH₂-cyclopropyl F
 229. H i-butyl n-propyl 2-tetrahydrofuranyl F230. H i-butyl n-propyl CH₂-2-tetra- F hydrofuran
 231. H i-butyln-propyl 2-tetrahydrothienyl F
 232. H i-butyl n-propyl CH₂OCH₃ Cl
 233. Hi-butyl n-propyl CH₃ Cl
 234. H i-butyl n-propyl CH₂OH Cl
 235. H i-butyln-propyl CH₂N(CH₃)₂ Cl
 236. H i-butyl n-propyl CH₂—N-piperdinyl Cl 237.H i-butyl n-propyl CH₂—N- Cl morpholinyl
 238. H i-butyl n-propylcyclopropyl Cl
 239. H i-butyl n-propyl CH₂-cyclopropyl Cl
 240. H i-butyln-propyl 2-tetrahydrofuranyl Cl
 241. H i-butyl n-propyl CH₂-2-tetra- Clhydrofuran
 242. H i-butyl n-propyl 2-tetrahydrothienyl Cl
 243. H i-butyln-propyl CH₂OCH₃ Br
 244. H i-butyl n-propyl CH₃ Br
 245. H i-butyln-propyl CH₂OH Br
 246. H i-butyl n-propyl CH₂N(CH₃)₂ Br
 247. H i-butyln-propyl CH₂—N-piperdinyl Br
 248. H i-butyl n-propyl CH₂—N- Brmorpholinyl
 249. H i-butyl n-propyl cyclopropyl Br
 250. H i-butyln-propyl CH₂-cyclopropyl Br
 251. H i-butyl n-propyl 2-tetrahydrofuranylBr
 252. H i-butyl n-propyl CH₂-2-tetra- Br hydrofuran
 253. H i-butyln-propyl 2-tetrahydrothienyl Br
 254. H i-butyl n-propyl CH₂OCH₃ I
 255. Hi-butyl n-propyl CH₃ I
 256. H i-butyl n-propyl CH₂OH I
 257. H i-butyln-propyl CH₂N(CH₃)₂ I
 258. H i-butyl n-propyl CH₂—N-piperdinyl I
 259. Hi-butyl n-propyl CH₂—N- I morpholinyl
 260. H i-butyl n-propylcyclopropyl I
 261. H i-butyl n-propyl CH₂-cyclopropyl I
 262. H i-butyln-propyl 2-tetrahydrofuranyl I
 263. H i-butyl n-propyl CH₂-2-tetra- Ihydrofuran
 264. H i-butyl n-propyl 2-tetrahydrothienyl I
 265. Hcyclobutyl n-propyl CH₂OCH₃ H
 266. H cyclobutyl n-propyl CH₃ H
 267. Hcyclobutyl n-propyl CH₂OH H
 268. H cyclobutyl n-propyl CH₂N(CH₃)₂ H 269.H cyclobutyl n-propyl CH₂—N-piperdinyl H
 270. H cyclobutyl n-propylCH₂—N- H morpholinyl
 271. H cyclobutyl n-propyl cyclopropyl H
 272. Hcyclobutyl n-propyl CH₂-cyclopropyl H
 273. H cyclobutyl n-propyl2-tetrahydrofuranyl H
 274. H cyclobutyl n-propyl CH₂-2-tetra- Hhydrofuran
 275. H cyclobutyl n-propyl 2-tetrahydrothienyl H
 276. Hcyclobutyl n-propyl CH₂OCH₃ CF₃
 277. H cyclobutyl n-propyl CH₃ CF₃ 278.H cyclobutyl n-propyl CH₂OH CF₃
 279. H cyclobutyl n-propyl CH₂N(CH₃)₂CF₃
 280. H cyclobutyl n-propyl CH₂—N-piperdinyl CF₃
 281. H cyclobutyln-propyl CH₂—N- CF₃ morpholinyl
 282. H cyclobutyl n-propyl cyclopropylCF₃
 283. H cyclobutyl n-propyl CH₂-cyclopropyl CF₃
 284. H cyclobutyln-propyl 2-tetrahydrofuranyl CF₃
 285. H cyclobutyl n-propyl CH₂-2-tetra-CF₃ hydrofuran
 286. H cyclobutyl n-propyl 2-tetrahydrothienyl CF₃
 287. Hcyclobutyl n-propyl CH₂OCH₃ F
 288. H cyclobutyl n-propyl CH₃ F
 289. Hcyclobutyl n-propyl CH₂OH F
 290. H cyclobutyl n-propyl CH₂N(CH₃)₂ F 291.H cyclobutyl n-propyl CH₂—N-piperdinyl F
 292. H cyclobutyl n-propylCH₂—N- F morpholinyl
 293. H cyclobutyl n-propyl cyclopropyl F
 294. Hcyclobutyl n-propyl CH₂-cyclopropyl F
 295. H cyclobutyl n-propyl2-tetrahydrofuranyl F
 296. H cyclobutyl n-propyl CH₂-2-tetra- Fhydrofuran
 297. H cyclobutyl n-propyl 2-tetrahydrothienyl F
 298. Hcyclobutyl n-propyl CH₂OCH₃ Cl
 299. H cyclobutyl n-propyl CH₃ Cl
 300. Hcyclobutyl n-propyl CH₂OH Cl
 301. H cyclobutyl n-propyl CH₂N(CH₃)₂ Cl302. H cyclobutyl n-propyl CH₂—N-piperdinyl Cl
 303. H cyclobutyln-propyl CH₂—N- Cl morpholinyl
 304. H cyclobutyl n-propyl cyclopropyl Cl305. H cyclobutyl n-propyl CH₂-cyclopropyl Cl
 306. H cyclobutyl n-propyl2-tetrahydrofuranyl Cl
 307. H cyclobutyl n-propyl CH₂-2-tetra- Clhydrofuran
 308. H cyclobutyl n-propyl 2-tetrahydrothienyl Cl
 309. Hcyclobutyl n-propyl CH₂OCH₃ Br
 310. H cyclobutyl n-propyl CH₃ Br
 311. Hcyclobutyl n-propyl CH₂OH Br
 312. H cyclobutyl n-propyl CH₂N(CH₃)₂ Br313. H cyclobutyl n-propyl CH₂—N-piperdinyl Br
 314. H cyclobutyln-propyl CH₂—N- Br morpholinyl
 315. H cyclobutyl n-propyl cyclopropyl Br316. H cyclobutyl n-propyl CH₂-cyclopropyl Br
 317. H cyclobutyl n-propyl2-tetrahydrofuranyl Br
 318. H cyclobutyl n-propyl CH₂-2-tetra- Brhydrofuran
 319. H cyclobutyl n-propyl 2-tetrahydrothienyl Br
 320. Hcyclobutyl n-propyl CH₂OCH₃ I
 321. H cyclobutyl n-propyl CH₃ I
 322. Hcyclobutyl n-propyl CH₂OH I
 323. H cyclobutyl n-propyl CH₂N(CH₃)₂ I 324.H cyclobutyl n-propyl CH₂—N-piperdinyl I
 325. H cyclobutyl n-propylCH₂—N- I morpholinyl
 326. H cyclobutyl n-propyl cyclopropyl I
 327. Hcyclobutyl n-propyl CH₂-cyclopropyl I
 328. H cyclobutyl n-propyl2-tetrahydrofuranyl I
 329. H cyclobutyl n-propyl CH₂-2-tetra- Ihydrofuran
 330. H cyclobutyl n-propyl 2-tetrahydrothienyl I
 331. Hcyclopropylmethyl- n-propyl CH₂OCH₃ H
 332. H cyclopropylmethyl- n-propylCH₃ H
 333. H cyclopropylmethyl- n-propyl CH₂OH H
 334. Hcyclopropylmethyl- n-propyl CH₂N(CH₃)₂ H
 335. H cyclopropylmethyl-n-propyl CH₂—N-piperdinyl H
 336. H cyclopropylmethyl- n-propyl CH₂—N- Hmorpholinyl
 337. H cyclopropylmethyl- n-propyl cyclopropyl H
 338. Hcyclopropylmethyl- n-propyl CH₂-cyclopropyl H
 339. H cyclopropylmethyl-n-propyl 2-tetrahydrofuranyl H
 340. H cyclopropylmethyl- n-propylCH₂-2-tetra- H hydrofuran
 341. H cyclopropylmethyl- n-propyl2-tetrahydrothienyl H
 342. H cyclopropylmethyl- n-propyl CH₂OCH₃ CF₃343. H cyclopropylmethyl- n-propyl CH₃ CF₃
 344. H cyclopropylmethyl-n-propyl CH₂OH CF₃
 345. H cyclopropylmethyl- n-propyl CH₂N(CH₃)₂ CF₃346. H cyclopropylmethyl- n-propyl CH₂—N-piperdinyl CF₃
 347. Hcyclopropylmethyl- n-propyl CH₂—N- CF₃ morpholinyl
 348. Hcyclopropylmethyl- n-propyl cyclopropyl CF₃
 349. H cyclopropylmethyl-n-propyl CH₂-cyclopropyl CF₃
 350. H cyclopropylmethyl- n-propyl2-tetrahydrofuranyl CF₃
 351. H cyclopropylmethyl- n-propyl CH₂-2-tetra-CF₃ hydrofuran
 352. H cyclopropylmethyl- n-propyl 2-tetrahydrothienylCF₃
 353. H cyclopropylmethyl- n-propyl CH₂OCH₃ F
 354. Hcyclopropylmethyl- n-propyl CH₃ F
 355. H cyclopropylmethyl- n-propylCH₂OH F
 356. H cyclopropylmethyl- n-propyl CH₂N(CH₃)₂ F
 357. Hcyclopropylmethyl- n-propyl CH₂—N-piperdinyl F
 358. H cyclopropylmethyl-n-propyl CH₂—N- F morpholinyl
 359. H cyclopropylmethyl- n-propylcyclopropyl F
 360. H cyclopropylmethyl- n-propyl CH₂-cyclopropyl F 361.H cyclopropylmethyl- n-propyl 2-tetrahydrofuranyl F
 362. Hcyclopropylmethyl- n-propyl CH₂-2-tetra- F hydrofuran
 363. Hcyclopropylmethyl- n-propyl 2-tetrahydrothienyl F
 364. Hcyclopropylmethyl- n-propyl CH₂OCH₃ Cl
 365. H cyclopropylmethyl-n-propyl CH₃ Cl
 366. H cyclopropylmethyl- n-propyl CH₂OH Cl
 367. Hcyclopropylmethyl- n-propyl CH₂N(CH₃)₂ Cl
 368. H cyclopropylmethyl-n-propyl CH₂—N-piperdinyl Cl
 369. H cyclopropylmethyl- n-propyl CH₂—N-Cl morpholinyl
 370. H cyclopropylmethyl- n-propyl cyclopropyl Cl
 371. Hcyclopropylmethyl- n-propyl CH₂-cyclopropyl Cl
 372. H cyclopropylmethyl-n-propyl 2-tetrahydrofuranyl Cl
 373. H cyclopropylmethyl- n-propylCH₂-2-tetra- Cl hydrofuran
 374. H cyclopropylmethyl- n-propyl2-tetrahydrothienyl Cl
 375. H cyclopropylmethyl- n-propyl CH₂OCH₃ Br376. H cyclopropylmethyl- n-propyl CH₃ Br
 377. H cyclopropylmethyl-n-propyl CH₂OH Br
 378. H cyclopropylmethyl- n-propyl CH₂N(CH₃)₂ Br 379.H cyclopropylmethyl- n-propyl CH₂—N-piperdinyl Br
 380. Hcyclopropylmethyl- n-propyl CH₂—N- Br morpholinyl
 381. Hcyclopropylmethyl- n-propyl cyclopropyl Br
 382. H cyclopropylmethyl-n-propyl CH₂-cyclopropyl Br
 383. H cyclopropylmethyl- n-propyl2-tetrahydrofuranyl Br
 384. H cyclopropylmethyl- n-propyl CH₂-2-tetra-Br hydrofuran
 385. H cyclopropylmethyl- n-propyl 2-tetrahydrothienyl Br386. H cyclopropylmethyl- n-propyl CH₂OCH₃ I
 387. H cyclopropylmethyl-n-propyl CH₃ I
 388. H cyclopropylmethyl- n-propyl CH₂OH I
 389. Hcyclopropylmethyl- n-propyl CH₂N(CH₃)₂ I
 390. H cyclopropylmethyl-n-propyl CH₂—N-piperdinyl I
 391. H cyclopropylmethyl- n-propyl CH₂—N- Imorpholinyl
 392. H cyclopropylmethyl- n-propyl cyclopropyl I
 393. Hcyclopropylmethyl- n-propyl CH₂-cyclopropyl I
 394. H cyclopropylmethyl-n-propyl 2-tetrahydrofuranyl I
 395. H cyclopropylmethyl- n-propylCH₂-2-tetra- I hydrofuran
 396. H cyclopropylmethyl- n-propyl2-tetrahydrothienyl I


10. A pharmaceutical composition, comprising: (a) a of a compound ofclaim 1; and (b) a pharmaceutically acceptable excipient.